11-(2-Hydroxyethylthio) prostenoic acid E and F series derivatives

ABSTRACT

This disclosure describes certain 11-(2-hydroxyethylthio) prostenoic acid E and F series derivatives, and their intermediates, useful as bronchodilators and inflammatory medeator release inhibitors.

RELATED APPLICATIONS

This application is a continuation-in-part of each of applications, Ser. Nos. 782,852 now abandoned and 782,853, now U.S. Pat. No. 4,085,272 both filed on Mar. 30, 1977.

BACKGROUND OF THE INVENTION

Applicants are not aware of any prior art reference which, in their respective judgments as one skilled in the prostaglandin art, would anticipate or render obvious the novel compounds of the instant invention; however, for the purpose of fully developing the background of the invention and establishing the state of the requisite art, the following reference is set forth:

U.S. Pat. No. 3,876,690, which discloses certain 11-(2-hydroxyethoxy)-9-keto and 9-hydroxy-prostenoic acid derivatives.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel 11-(2-Hydroxyethylthio)13-trans-prostenoic acids and esters as well as to the cyclopentenone intermediates and processes for their preparation. The novel compounds of this invention embrace all the possible optical isomers, diastereomers and enantiomers, racemates, and racemic mixtures represented by the following general formulae of the naturally occurring mammalian prostaglandins.

The first embodiment of the invention is represented by an optically active compound of the formula: ##STR1## wherein G is a moiety selected from the group consisting of ##STR2## Z is a divalent moiety selected from the group consisting of --(CH₂)₆ -- and ##STR3## R₁ is selected from the group consisting of hydroxy and C₁ -C₆ alkoxy; and R is a moiety selected from the group consisting of: ##STR4## wherein R₄ is selected from the group consisting of hydrogen and methyl, R₅ is selected from the group consisting of C₄ -C₇ alkyl and 2-cis (C₄ -C₆) alkenyl, R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ is selected from the group consisting of C₁ -C₂ alkyl; and R₁₁ is selected from the group consisting of C₃ -C₇ alkyl; with the proviso that when R₅ is 2-cis(C₄ -C₆) alkenyl then R₄ must be hydrogen and Z must be ##STR5## the racemic mixture thereof; the mirror image thereof; and when R₁ is hydroxy, the pharmaceutically acceptable salts thereof.

The second embodiment of this invention is represented by an optically active compound of the formula: ##STR6## wherein G is a moiety selected from the group consisting of ##STR7## Z is a divalent moiety selected from the group consisting of --(CH₂)₆ -- and ##STR8## R₁ is selected from the group consisting of hydroxy and C₁ -C₆ alkoxy; and R is a moiety selected from the group consisting of ##STR9## wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₇ is selected from the group consisting of C₂ -C₄ alkyl, R₁₀ is selected from the group consisting of C₁ -C₄ alkyl, R₁₁ is selected from the group consisting of C₃ -C₇ alkyl and R₁₂ is selected from the group consisting of C₁ -C₃ alkyl; the racemic mixture thereof; the mirror image thereof; and when R₁ is hydroxy, the pharmaceutically acceptable salts thereof.

The third embodiment of this invention is represented by an optically active compound of the formula: ##STR10## wherein G is a moiety selected from the group consisting of ##STR11## z is a divalent moiety selected from the group consisting of --(CH₂)₆ -- and ##STR12## R₁ is selected from the group consisting of hydroxy and C₁ -C₆ alkoxy; and R is a moiety selected from the group consisting of ##STR13## wherein R₆ is selected from the group consisting of C₃ -C₅ alkyl, R₈ is selected from the group consisting of C₁ -C₂ alkyl and R₁₁ is selected from the group consisting of C₃ -C₇ alkyl; the racemic mixture thereof; the mirror image thereof; and when R₁ is hydroxy, the pharmaceutically acceptable salts thereof.

The fourth embodiment of the invention is represented by a compound of the formula: ##STR14## wherein Z is a divalent moiety selected from the group consisting of --(CH₂)₆ -- and ##STR15## R₁ is slected from the group consisting of hydroxy, C₁ -C₆ alkoxy, triloxy, tetrahydropyranyloxy and tri-(C₁ -C₆) alkylsilyloxy; and R₂ is selected from the group consisting of hydrogen, trityl, tetrahydropyranyl and tri-(C₁ -C₆) alkylsilyl.

In a further embodiment of the invention, the 11-(2-hydroxyethylthiol) group in each of the compounds described herein may be replaced by other thio radicals having the general formula R₁₃ S-- wherein R₁₃ is an alkyl group of one to eight carbon atoms or an aryl group, each may have one or more substituents thereon selected from the class consisting of hydroxy, mercapto, carboxy, carboalkoxy and amino. This embodiment includes compounds of the formula: ##STR16## wherein G , Z, R and R₁ are defined in the foregoing embodiments, and Y is R₁₃ S-as defined above. For example, Y may be selected from the group consisting of ##STR17##

Useful pharmacologically acceptable salts of the above formula, where R₁ is hydroxyl, are those with pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations.

Preferred metal cations are those derived from the alkali metals, e.g. lithium, sodium and potassium, and from the alkaline earth metals, e.g. magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines such as mono-, di- or trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, mono- or dibenzylamine, α- or β-phenylethylamine, ethylenediamine, diethylenetriamine, and araliphatic amines containing up to and including 18 carbon atoms, as well as heterocyclic amines, e.g. piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivatives thereof, e.g. 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, e.g. mono-, di-, or triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxy-methyl) aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

The compounds of this invention are administered in various ways for various purposes, e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, bucally, sublingually, topically and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose it is preferred, because of increased water solubility, that R₁ be hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used. On certain occasions it may be advantageous to administer the compounds of this invention as clathrate compounds with substances such as a-cyclodextrin.

DETAILED DESCRIPTION OF THE INVENTION

The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinephrine-induced mobilization of free fatty acids, and have other pharmacological and autopharmacological effects in mammals. See Bergstom, et. al., J. Biol. Chem., 238, 3555 (1963) and Horton, Experientia, 21, 113 (1965) and references cited therein. All of the so called natural prostaglandins are derivatives of prostanoic acid: ##STR18## The hydrogen atoms attached to C-8 and C-12 are in transconfiguration. The natural prostaglandins represent only one of the possible optical isomers. The compounds of this invention include all possible optical isomers and racemates.

The configuration of substituents on the prostaglandin molecule are designed to be in the α-configuration if they lie beneath the plane of the molecule as drawn above and are designated with a ---- bond. Those substituents which lie above the plane of the molecule as drawn above are designated β and are represented by a bond. ##STR19##

The natural PGE₁, PGE₂ and PGE₃ compounds are potent in causing multiple biological responses, even at low doses. As a bronchodilator, the natural prostaglandins have an inconveniently short duration of activity. In striking contrast, the novel 11-deoxy-11α/β-(2-hydroxyethylthio) PGE analogs of this invention possess a significantly longer duration of bronchodilation in the guinea pig Konzett assay.

Bronchodilator activity is determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine of acetylcholine by the Konzett procedure. [See J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995 (1968)].

In the Table I which follows, bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ED₅₀ determined from the results obtained with three logarithemic cumulative intravenous doses.

                                      TABLE I                                      __________________________________________________________________________     Compound            ED.sub.50 in mg/kg                                         Tested              5-HT                                                                               HIST.                                                                              ACH.                                                                               Potency (Range 0-4)                            __________________________________________________________________________     l-11α/β-(2-hydroxyethylthio)-11-deoxy-                                                   8.8.sup.-3                                                                         4.24.sup.-3                                                                        27.5.sup.-3                                       PGE.sub.2 methyl ester (Example 223)                                                                   44.2.sup.-3                                                                        391.sup.-3                                                                         4                                              l 11α-(2-hydroxyethylthio)-11-deoxy-                                                         5.9.sup.-3                                                                         4.87.sup.-3                                                                        11.1.sup.-3                                        PGE.sub.2 methyl ester (Example 229)                                                               35.sup.-3   4                                              l 11β-(2-hydroxyethylthio)-11-deoxy-                                                          60.sup.-3                                                                          45.5.sup.-3                                                                        62.8.sup.-3                                        PGE.sub.2 methyl ester (Example 229)                                                                       671.sup.-3                                                                         4                                              l 11α/β-(2-hydroxyethylthio)-11,deoxy-                                                  5.5.sup.-3                                                                         4.7.sup.-3                                                                         11.sup.-3                                          PGE.sub.1 (Example 228)                                                                            34.sup.-3                                                                          36..sup.-3                                                                         61.sup.-3                                                              78.sup.-3                                                                          71.sup.-3                                                                          221.sup.-3                                                                         4                                              dl 11α/β-(2-hydroxyethylthio)-11,15-                                                    19.sup.-3                                                                          19.5.sup.-3                                                                        53.sup.-3                                          bisdeoxy-16-hydroxy-PGE.sub.1 (Example 226)                                                        82.sup.-3                                                                          150.sup.-3                                                                 288.sup.-3  3                                              dl 11α/β-(2-hydroxyethylthio)-11,15-                                                    17.sup.- 3                                                                         20.sup.-3                                                                          34.sup.-3                                          bisdeoxy-16-hydroxy-16-methyl-PGE.sub.2                                                            77.sup.-3                                                                          108.sup.-3                                             (Example 225)       257.sup.-3  3                                              __________________________________________________________________________

In addition, compounds of this invention possess the additional ability to function as inflammatory medeator release inhibitors as assayed using sensitized human basophiles.

The novel compounds of the present invention can be readily prepared from certain PGA derivatives which may be represented by the following general formula: ##STR20## wherein R, R₁, and Z are as hereinabove described.

The preparation of the requisite PGA intermediates from the corresponding PGE compounds is described [Corey, E. J., Jour. Amer. Chem. Soc., 90, 3245 (1968)], or can be obtained by analogous procedures to those described in the aforesaid reference.

The 11-(2-hydroxyethylthio)-prostenoic acids and esters of this invention may be prepared by addition of 2-mercoptoethanol to the PGA derivative in the presence of a catalytic amount of an organic base such as triethylamine. In the absence of a catalysis, the reaction proceeds slowly. The product is obtained as a mixture of epimers at C-11 which are readily separable by column chromatography on silica-gel.

It has been found, however, if the amount of catalysis is increased, or the reaction temperature is increased, or the duration of the reaction is increased, then the 11α-isomer product will predominate over the 11β-isomer.

The novel compounds of this invention can also be prepared by 1,4-conjugate addition involving treatment of the ether blocked cyclopentenone (71) with a lithio-cuprate reagent such as (68), (69), or (70) prepared as illustrated in Flowsheets A through H.

The 1,4-conjugate additionprocedure is described hereinbelow in Flowsheet H. The preparation of the various requisite 1-iodo-trans-1-alkenyl or 1-tributylstannyl-trans-1-alkenyl derivative is illustrated in Flowsheets A through F and the novel and important synthesis of 4-(2-hydroxyethylthio)-cyclopentenone is described in connection with Flowsheet G. ##STR21##

In accordance with the scheme as outlined hereinabove in Flowsheet A, carbethoxycyclobutane is converted to its enolate anion (2) by treatment with a strong base such as lithium cyclohexylisopropylamide, prepared from the corresponding amine and n-butyl lithium (hexane solution) in a solvent, such as anhydrous tetrahydrofuran, at very low temperatures, such as 78° C. The resulting enolate anion (2) is then alkylated with R₁₁ -X (3) to provide (4), the ester group of which is reduced to alcohol (5) by reaction with 2 equivalents of diisobutyl aluminum hydride, lithium aluminum hydride or the like. Oxidation of alcohol (5) with dipyridine chromium oxide complex ["Reagents for Organic Synthesis", L. F. Fieser and M. Fieser, John Wiley and Sons, Inc., New York, 4, 215 (1974)], prepared in situ in methylene chloride solution, provides the corresponding aldehyde (6), which can also be obtained directly from ester (4) by partial reduction with one equivalent of diisobutyl aluminum hydride at -78° C., but the former two-step procedure is preferable. Reaction of aldehyde (6) with lithium acetylide ethylene diamine complex provides the 3-hydroxy-1-alkyne (7), which is converted to its trimethylsilyl ether in the usual manner. The silylated derivative is then treated with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures from 2-methyl-2-butene, sodium borohydride and boron trifluoride etherate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an agueous solution of sodium hydroxide to give the 1-iodo-3-trimethylsilyloxy-4,4-trimethylene-1-alkene (8). ##STR22##

In accordance with the scheme as outlined hereinabove in Flowsheet B, 1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne (9) is treated with n-butyllithium at -78° C. and then with a freshly prepared solution of zinc iodide in anhydrous tetrahydrofuran, also at -78° C. Reaction of aldehyde (10) with the resulting reagent then provides the 4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11). This reaction procedes with great stereoselectivity and the product (11) is in the erythro configuration. [For additional information concerning this reaction see the examples which follow and F. Mercier, R. Epstein and S. Holland, Bull. Soc. Chim. France, 690 (1972).]

The tetrahydropyranyl group in (11) is removed on weak acid treatment and the resulting erythro diol (12) can be reblocked by treating with an appropriate aldehyde or ketone ##STR23## in the presence of strong acid catalyst in the usual way to give the ketal or acetal (13). Acetone is a useful ketone for this purpose and the product (13) is then a 3,4-isopropylidenedioxy-1-alkyne. It is also possible to utilize silyl blocking groups (introduced after removal of the 1-trimethylsilyl group) to ultimately give the vinyl iodides (16) or (17). Weak base treatment of (13), for example heating for about one hour in refluxing methanol with potassium carbonate, results in desilylation to give (14). The 1-alkene (14) is converted to the corresponding 1-iodo-trans-1-alkene (15) by treatment with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures from 2-methyl-2-butene, sodium borohydride and boron trifluoride etherate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give (15).

For the preparation of the threo derivatives, the 4-hydroxy-3-tetrahydropyranyloxy-1-alkyne (11) is acetylated to provide the corresponding 4-acetoxy derivative (18). The tetrahydropyranyl group is preferentially hydrolyzed with weak acid to (19), which is then tosylated in the usual manner to afford the erythro-3-tosyloxy-4-acetoxy-1-alkyne (20). Solvolysis of (20) under essentially neutral conditions by heating in aqueous tetrahydrofuran in the presence of an isoluble acid-acceptor, such as calcium carbonate, results in inversion of C₃, furnishing the threo-3-hydroxy-4-acetoxy-1-alkyne (21), which is then deblocked with aqueous base to give the threo-3,4-diol (22). Diol (22) is converted to an acetal or ketal (23) (or silyl derivatives as in (16) or (17)]and thence to the 1-iodo-trans-1-alkene (16) as described hereinabove wherein Ra is lower alkyl (C₁ to C₃).

For the preparation of the 16-alkoxyprostanoic acids of this invention, the erythro-4-hydroxy-3-terahydropyranyloxy-1-alkyne (11) is desilylated by methanol-potassium carbonate treatment and the resulting (25) is etherified to give the 4-alkoxy-3-tetrahydropyranyloxy-1-alkyne (26). A useful procedure for this last step involves treatment of (25) with a molar equivalent of sodium hydride to give the 4-alkoxide which is then alkylated with the appropriate alkylating agent, for example methyl iodide. The 4-alkoxy-1-alkyne (26) is then converted to the corresponding 1-iodo-trans-1-alkene (27) as described hereinabove for the preparation of (15). If desired with tetrahydropyranyl blocking group in (27) can be hydrolyzed (weak acid) and the resulting free 3-ol corresponding to (27) converted to the 3-trimethylsilyloxy derivative (28), all in the usual manner wherein R₈ is lower alkyl (C₁ to C₃).

For the threo series, the tetrahydropyranyl group in erythro-4-alkoxy-1-alkyne (26) is cleaved and the resulting 3-hydroxy-4-alkoxy-1-alkyne (29) is tosylated to give the erythro-3-tosyloxy-4-alkoxy-1-alkyne (30). S_(n) 2 displacement reaction with (30) with reagents such as tetrahydroammonium formate results in inversion to the threo derivative (31) saponification of which provides threo-3-hydroxy-4-alkoxy-1-alkyne (32). Trimethylsilylation followed by the vinyl iodide conversion procedure described hereinabove furnishes the threo-1-iodo-1-alkene (33) wherein R₈ is hydrogen or lower alkyl (C₁ to C₃).

The 15-alkyl and/or 16-alkyl derivatives of this invention can be prepared by substituting ##STR24## for (4) and/or ##STR25## for (6) (R'₅ =lower alkyl of 1 to 3 carbons) in Flowsheet B.

In accordance with the procedure as outlined in Flowsheet C, an aldehyde (34) is treated with propargylic magnesium halide to form the homopropargylic alcohol (35), which is converted to its trimethylsilyl ether in the usual manner. The silylated derivative is then treated with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperature from 2-methyl-2-butene, sodium borohydride and boron trifluoride etherate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give the 1-iodo-4-trimethylsilyloxy-trans-1-alkene (36), precursors for 16-hydroxy-prostaglandin.

The trimethylsilyl protecting group is removed with mild acid and the resulting vinyl iodide alcohol is oxidized with pyridinium chlorochromate to provide the 1-iodo-4-oxo-trans-1-alkene (37), which upon treatment with a Grignard reagent (R₁₂ MgX) provides the 1-iodo-4-hydroxy-trans-1-alkene, which is silylated in the usual manner to provide the silyl ether (38) wherein R₁₁ is lower alkyl (C₃ to C₇) and R₁₂ is vinyl or cyclopropyl. ##STR26##

A more preferred method for the preparation of vinyllithium precursor is also described in Flowsheet C. Treatment of the requisite carboxylic acid (39a or 39) with the appropriate organolithium reagent (R₁₂ Li or R₁₁ Li respectively), wherein R₁₁ and R₁₂ are hereinabove defined, give the corresponding ketone (40) which upon treatment with propargylic magnesium halide provides the homopropargylic alcohol (41) which is converted to the trans vinylstannyl derivative by sequential treatment with chlorotrimethylsilane and tri-n-butyltin hydride. Treatment of the vinylstannyl reagent (42) with n-butyllithium at a temperature of -10° C. to -78° C. generates the corresponding vinyllithium reagent. ##STR27##

In accordance with Flowsheet D hereinabove, the precursors for other 16-hydroxy prostaglandins are prepared by treating an appropriate aldehyde or ketone (43) with a propargylic magnesium halide to yield the requisite homoproparylic alcohol (44). The alcohol is protected as a tritylether (45) (for secondary alcohols) or as a trimethylsilylether (45) (for tertiary alcohols). These ethers are then converted to the appropriate trans-vinyliodide (46) by treatment with disiamylborane generated in situ from 2-methyl-2-butene, sodium borohydride, and boron trifluoride, follwoed by treatment with trimethylamine oxide and then iodine and sodium hydroxide, wherein R₁₃ is hydrogen and methyl, T is O-C(C₆ H₅)₃ when R₁₃ is hydrogen and T is O-Si(CH₃)₃ when R₁₃ is methyl; R₁₄ is selected from the group comprising lower alkyl (C₃ to C₅), lower 1-alkenyl (C₃ to C₅), ##STR28## wherein R₇ is as described above; with the provision that when R₁₄ is ##STR29## then R₁₃ must be hydrogen. ##STR30##

The preparation of the precursors for the synthesis of 16-aryloxy and 17-phenyl congeners is described in accordance with Flowsheet E hereinabove. The aryl esters (49) are prepared by esterifying the commerically available acids or by treatment of ethyl bromoacetate with the appropriate phenol. The ester (49) is carefully reduced to the aldehyde (50) which upon treatment with lithium acetylide provides the propargylic alcohol (51). Treatment of the alcohol (51) with chlorotrimethylsilane followed by tri-n-butyltin hydride furnishes the requisite vinylstannyl derivative (53). Similar treatment starting with substituted hydrocinnamaldehyde (50a) provides the respective vinylstannyl derivative (53a).

The preparation of the precursors for the synthesis of secondary 15-hydroxy congeners are described in the literature. The preparation of the precursor for 15-methyl-15-hydroxy is described in Flowsheet F hereinbelow. In accordance with Flowsheet F, an acid chloride, wherein R₅ is hereinabove defined, is treated with acetylene and aluminum trichloride to provide the vinylchloride (55) which upon treatment with sodium iodide furnishes the vinyliodide (56). Treatment of (56) with methylmagnesium halide followed by chlorotrimethylsilane gives the requisite protected vinyliodide (57). ##STR31##

Certain of the requisite 4-(2-hydroxyethylthio)-cyclopentenones may be prepared from the corresponding 4-hydroxy or alkoxy cyclopentenones Ia in accordance with the reaction scheme of Flowsheet G or from the 3-hydroxy cyclopentenones Ib, also described in Flowsheet G.

The requisite 4-alkoxy cyclopentenones are described in U.S. Pat. No. 3,876,690 or can be obtained by analogous procedures to those described in the aforesaid patent. The 3 and 4-hydroxy-cyclopentenones are described in U.S. Pat. No. 3,966,773 and U.S. Pat. No. 3,952,033. ##STR32##

In accordance with the scheme as outlined hereinabove in Flowsheet G wherein R₃ is triloweralkylsilyl, tetrahydropyranyl or triphenylmethyl, R₁ ' is C₁ -C₆ alkoxy, tetrahydropyranyloxy, triloweralkylsilyloxy, or triphenylmethoxy and R₄ and R₁ are hereinabove defined, the cyclopentenones Ia or Ib are treated with 1-equivalent of 2-mercoptoethanol in the presence of sodium methoxide and methanol for between 1-5 hours at room temperature affording the 4-(2-hydroxyethylthio)-cyclopentenones (II), which are converted into their trimethysilyl, tetrahydropyranyl or triphenylmethyl ether esters (III) in the usual manner.

The preparation of the prostaglandin congeners of this invention are described in Flowsheet H wherein R' is selected from the group consisting of: ##STR33## wherein R₅, R₆, R₇, R₈, R₁₀, R₁₁, and R₁₂ are as hereinabove defined, and p is 1 or 2.

In accordance with Flowsheet H, a suitably protected vinyliodide (65) is treated with either one equivalent of n-butyllithium or 2 equivalents of t-butyllithium at low temperature, preferably -30° to -78° C. in an inert solvent, eg. hexane, ether or toluene to provide the trans-alkenyllithium reagent (67).

Alternatively, the vinyllithium reagent (67) can be prepared by treatment of a vinylstannyl derivative such as (66) with n-butyllithium at -10° to -78° C.

For the preparation of the asymmetrical lithio cuprate (68) or the like, a solution of one molar equivalent of copper (I)-1-alkyne, preferable copper (I)-1-pentyne in anhydrous tributyl phosphine, preferably one to five molar equivalents, and anhydrous ether is added to one molar equivalent of the aforementioned vinyllithium solution cooled to about -79° C. After about one hour at this temperature, a molar equivalent of the requisite cyclopentenone (71) is added. After several hours at -30° C. to -70° C. the reaction mixture is quenched with aqueous ammonium chloride solution and the blocked product (72) is isolated in the usual manner.

It is also possible to effect conjugate 1,4-addition with the asymmetrical lithio cuprate (70) derived from vinyllithium (67) and cuprous throphenoxide. A solution of vinyllithium (67) in ether at -78° C. is reacted with an equimolar amount of a reagent prepared by admixture, in ether at a temperature of 0° C. to -78° C., of equimolar amounts of cuprous thiophenoxide and copper (I) iodide tributylphosphonium complex. After about 30 minutes at this temperature, the lithio cuprate (70) is treated with the requisite cyclopentenone (71) as described hereinabove for the conjugate addition with 1-alkynyl lithio cuprate (68).

For the preparation of the symmetrical lithio cuprate (69) one molar equivalent of copper (I) iodide tributylphosphine complex, dissolved in anhydrous ether, is added at about -78° C. to two molar equivalents of the aforementioned vinyl iodide (65) solution in hexanes, cooled to -78° C. After about one hour at this temperature, the lithio cuprate (69) is treated with the requisite cyclopentenone (71) as described hereinabove, for the conjugate addition with the 1-alkynl lithio cuprate (68).

The procedures for conjugate addition involving organocopper reagents are well known in the art, see for example, C. J. Sih, et. al., J. A. C. S., 97, 865 (1975).

In the cases where R₁ '=trimethylsilyloxy in cyclopentenone (71) the conjugate addition is performed at -78° C. to -40° C. The reaction is quenched by addition of an ether solution of acetic acid. Removal of blocking groups is then carried out as described in the reference above to provide the product (73) wherein R₁ and R are hereinabove described.

All available evidence leads us to believe that the β-chain introduced by the cuprate process occupies a position trans to the 11-oxy function. Similarly, we are led to the conclusion that in the product (73) the two side-chains attached to C₈ and C₁₂ are trans to each other. However, we are not certain of this configurational relationship in the product as it is obtained directly from the cuprate process. These products may have the side-chain in a trans or cis-relationship or they may be a mixture containing both the trans- and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation 8ε. In order to ensure a trans-relationship in (73) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE₁ to a mixture containing about 90% of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature. ##STR34##

The 9-keto derivatives of this invention can be converted to the corresponding 9-hydroxy derivatives as described in Flowsheet I. If this conversion is effected with sodium borohydride, the product is a mixture of 9α- and 9β-hydroxy derivatives (75) and (76) respectively, as set forth in the following reaction scheme, wherein R₁, R and Z are as hereinabove defined. ##STR35##

When the reaction is carried out with lithium perhydro-9β-boraphenalyl hydride [H. C. Brown and W. C. Dickason, J.A.C.S., 92, 709 (1970)] or lithium tris-(t-butyl)-borohydride [H. C. Brown and S. Krishnamurthy, ibid., 94, 7159 (1972)] the product is at least predominantly the 9α-hydroxy derivative wherein the 9-hydroxy group is cis to the side chain attached to C8 and to the 11-mercapto function. In accordance with accepted convention, an α-substituent at the 8-, 9-, 11- or 12-positions is behind the plane of the paper, whereas a β-substituent at these positions is in front of the plane of paper. This is usually represented by a--bond for an α-substituent, a bond for a β-substituent, and a bond where both are indicated.

The carboxylic acids of this invention can be readily converted to the various alkyl esters of this invention by treatment in the usual manner with the appropriate diazoalkane. The preparation of diazoalkanes by various procedures are well described in the art. See for example, C. D. Gutsche, Organic Reactions, 8, 389 (1954). Certain of the esters of this invention can also be obtained directly by use of the appropriate cyclopentenone ester. The various esters can also be prepared by any of several procedures well-known in the art via an acid chloride (prior blocking of free alcohol groups with appropriate blocking groups such as trialkylsilyl, tetrahydropyranyl and the like) or mixed anhydrides and treatment of these intermediates with the appropriate alcohol. Mixed anhydrides can be obtained by treatment of the prostaglandin acid in a solvent such as dioxane at a temperature in the range of 0° C. to 15° C. with a molar equivalent of a tri-alkylamine, preferably triethylamine, tributylamine and the like, and then a molar equivalent of isobutyl chlorocarbonate or the like. The resulting mixed anhydrides is then treated with the appropriate alcohol to give the derivatized product. [For a pertinent literature analogy see Prostaglandins, 4, 738 (1973).]

An alternative procedure involves treatment of the prostaglandin acid with a molar equivalent of the trialkylamine in an excess of the appropriate alcohol in an anhydrous solvent such as methylene chloride, a molar equivalent of p-toluenesulfonyl chloride is then added (if necessary, a second molar equivalent can be added) and after stirring at ambient temperatures for about 15 minutes to one hour the product is worked-up in the usual manner. (For a pertinent literature analogy, see U.S. Pat. No. 3,821,279.) A third procedure involves the use of dicyclohexylcarbodiimide in the usual manner; for a pertinent literature analogy see German Offen. No. 2,365,205; Chem. Abst., 81, 120098g (1974).

The esterified alcohol derivatives of this invention are also prepared in the usual manner by procedures well known in the art from the appropriate alkanoic acid anhydride or acid chloride.

When the compounds of this invention are prepared from racemic starting compounds, two racemates are obtained. In appropriate instances these racemates may be separated from each other by careful application of the usual chromatographic procedures. In the more difficult instances it may be necessary to apply high pressure liquid chromatography including recycling techniques. [see G. Fallick, American Laboratory, 19-27 (August 1973) as well as references cited therein. Additional information concerning high speed liquid chromatography and the instruments necessary for its application is available from Water Associate Inc., Maple Street, Mildord, Mass.]

In addition, optically active congeners can be prepared by treating a racemic mixture of a cyclopentenone (71) with the cuprate derived from an optically active vinyliodide such as (77) to give two diasteriomers (78) and (79) as shown in Flowsheet J. Chromatographic separation by the usual methods, after removal of the protecting groups, will then provide both the nat (78) and ent (79) epimers possessing the same absolute configuration at the carbon bearing the hydroxyl vinyl cuprate precursor.

Methods for the resolution of the vinyliodides or precursors to the vinyliodides such as propargylic or homopropargylic alcohols are known in the art. [J. Fried, et. at., Annals. New York Acadamy of Science, 180, 60 (1971); R. Pappo, et. al., Ibid, 180, 66 (1970); A. F. Kluge, et. al., J.A.C.S., 94, 7827 (1972); U.S. Pat. No. 3,950,446]. ##STR36##

EXAMPLE 1 Preparation of ethyl 2,2-trimethylenehexanoate

To a stirred solution of 27.6 g of freshly distilled N-isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran cooled to -78° C. is added at a fast rate 96 ml of 2.04 M n-butyllithium in hexane. To the resulting solution is added dropwise 25 g of ethyl cyclobutanecarboxylate. After 30 minutes the resulting solution is allowed to warm to ambient temperature, is transferred to a dropping funnel under nitrogen and is added dropwise over a period of 11/4 hours to a solution of 54 g of n-butyl iodide in 100 ml of dry dimethylsulfoxide maintaining the temperature at 16°-20° C. Stirring is continued for an additional 30 minutes. The separated salts are removed by filtration, the mother liquor is taken to a small volume and the resulting oil is diluted with hexanes. This solution is washed with 2% hydrochloric acid, saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent is removed and the residual oil is distilled to give 14.6 g (41 %) of product, bp 84°-87° C. (10 mm).

EXAMPLE 2 Preparation of ethyl 2,2-tetramethylenehexanoate

In the manner described in Example 1, treatment of the lithium salt of ethyl cyclopentanecarboxylate with n-butyl iodide furnishes the subject product.

EXAMPLE 3 Preparation of 2,2-trimethylenehexan-1-ol

To a stirred solution of 20 g of ethyl 2,2-trimethylenehexanoate (Example 1) in 100 ml of dry toluene, in an argon atmosphere and cooled in an ice bath, is added dropwise 250 ml (2 molar equivalents) of 0.89 M diisobutylaluminum hydride in toluene. The resulting solution is stirred at ambient temperature for 2 hours and then poured into excess iced 5% hydrochloric acid. The organic phase is separated and washed with 5% hydrochloric acid, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 14.8 g (96%) of oil; bp 92°-93° C. (10 mm).

EXAMPLE 4 Preparation of 2,2-tetramethylenehexan-1-ol

In the manner described in Example 3, treatment of ethyl 2,2-tetramethylenehexanoate (Example 2) with 0.89 molar diisobutylaluminum hydride furnishes the subject product.

EXAMPLE 5 Preparation of 2,2-trimethylenehexaldehyde

Chromium trioxide (61.5 g), dried in a vacuum desiccator over phosphorous pentoxide, is added to an ice cold solution of 97 g of dry pyridine in one liter of dry methylene chloride. The deep red suspension is stirred for 15 minutes at 0° C. and then for 45 minutes at ambient temperature. A solution of 14.5 g of 2,2-trimethylenehexanol-1 (Example 3) in 55 ml of methylene chloride is added all at once to the suspension. A black tarry deposit is formed immediately. After stirring at ambient temperature for 15 minutes the solution is decanted from the tarry deposit which is then triturated four times with small portions of methylene chloride. The combined extracts are washed twice with ice cold 5% sodium hydroxide, ice cold 5% hydrochloric acid and finally with saturated sodium chloride solution, dried with magnesium sulfate and taken to dryness. Distillation gives 12.9 g of product; bp 69° C. (11 mm).

EXAMPLE 6 Preparation of 2,2-tetramethylenehexaldehyde

Oxidation of 2,2-tetramethylenehexan-1-ol (Example 4) with chromium trioxide-pyridine complex in the manner described in Example 5 furnishes the subject product.

EXAMPLE 7 Preparation of 4,4-trimethylene-1-octyn-3-ol

To a solution of lithium acetylide-ethylenediamine complex (9.4 g) in 90 ml of dry dimethylsulfoxide, cooled in an ice bath, is added 12.94 g of 2,2-trimethylenehexaldehyde (Example 5) in 10 ml of dimethylsulfoxide dropwise, at such a rate that the temperature is maintained at 20°-25° C. The solution is stirred at ambient temperature for 12 hours and then poured into a mixture of ice cold 2% hydrochloric acid and ether. The ether layer is separated and the aqueous phase is extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation provides 13.53 g of product; bp 108°-109° C. (13 mm).

EXAMPLE 8 Preparation of 4,4-tetramethylene-1-octyn-3-ol

Treatment of 2,2-tetramethylenehexaldehyde (Example 6) with lithium acetylide-ethylenediamine complex in dimethylsulfoxide in the manner described in Example 4 is productive of the subject compound.

EXAMPLE 9 Preparation of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne

To a stirred solution of 5.3 g of 4,4-trimethylene-1-octyn-3-ol (Example 7) and 5.42 g of imidazole in 32 ml of dry dimethylformamide, cooled in an ice bath under argon atmosphere is added 4.35 g of chlorotrimethylsilane. After stirring at 0° C. for 15 minutes, the solution is stirred at ambient temperature for 18 hours and then poured into 200 ml of hexanes. The solution is washed twice with ice cold water, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation furnishes 6.02 g (80%) of colorless oil; bp 110°-112° C. (14 mm).

EXAMPLE 10 Preparation of 4,4-tetramethylene-3-trimethylsilyloxy-1-octyne

Treatment of 4,4-tetramethylene-1-octyn-3-ol (Example 8) with chlorotrimethylsilane in dimethylformamide containing imidazole as described in Example 5 furnishes the subject product.

EXAMPLE 11 Preparation of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne

To a solution of 25 g of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 9), stirred under argon atmosphere at -78° C., is added dropwise 93 ml of 2.3 M n-butyllithium in hexane at a rate to maintain the temperature below -40° C. After stirring for 40 minutes, a solution of iodine is allowed to warm to ambient temperature and 10% aqueous sodium thiosulfate solution is added until the purple color is removed. The organic phase is washed with dilute aqueous sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and taken to dryness to afford the subject product as an oil.

EXAMPLE 12 Preparation of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-cis-octene

To a solution of 30 g of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 10) in 100 ml of methanol, under argon atmosphere is added 54 g of potassium azodicarboxylate [J. Thiele, Annalen der Chemie, 271, 127 (1892)]. To this solution is added dropwise 45 ml of acetic acid over a period of about 2 hours. The solids are removed by filtration and the mother liquor is reduced to a small volume, diluted with water and extracted with ether. The ether is evaporated and the residual oil is stirred with 250 ml of 1 M sodium bicarbonate solution. The solution is extracted several times with ether and the combined extracts are washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and taken to dryness to furnish the subject product as an oil.

EXAMPLE 13 Preparation of 1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-trans-octene

To a mixture of 4.76 g of sodiumborohydride and 23.6 g of 2-methyl-2-butene in 220 ml of dry tetrahydrofuran at -5° C. is added dropwise 23.8 g of freshly distilled borontrifluoride etherate. The resulting mixture is stirred at -5° C. to -0° C. for 2 hours and to it is added dropwise a solution of 20 g of 4,4-trimethylene-3-trimethylsilyloxy-1-octyne (Example 12) in 20 ml of dry tetrahydrofuran. The resulting mixture is stirred at ambient temperature for 21/2 hours. The mixture is then cooled to -5° C. and there is added 44 g of trimethylene oxide protionwise over a period of 20 minutes, maintaining the temperature at 15°-20° C. The mixture is stirred at ambient temperature for 2 hours and then poured simultaneously, with a solution of 119 g of iodine in 290 ml of tetrahydrofuran, into 1490 ml of 15% aqueous sodium hydroxide solution. After stirring for 30 minutes the organic phase is separated and he aqueous phase is extracted with ether. The combined organic phase is washed with 5% aqueous sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 27 g of oily material. Chromatography on 135 g of florisil and eluting with 500 ml of hexanes furnishes 24 g of oily product which is shown to be contaminated with starting material and iodoform by infrared and thin layer chromatography. The material is purified by removing the trimethylsilyl group in the following manner. The crude product is dissolved in 350 ml of acetic acid-tetrahydrofuran-water (4:2:1) by stirring at ambient temperature for 5 minutes. The solvent is removed under reduced pressure and the residual oil containing mainly 1-iodo-3-hydroxy-4,4-trimethylene-1-trans-octene is applied to a 2" (flat) dry column containing 1200 g of Woelm silica gel. The column is developed with benzene, cut into one-inch segments and each segment is eluted with chloroform. Combination of the appropriate fractions affords 300 mg of iodomethane, 2.8 g of 4,4-trimethylene-1-octyne-3-ol, and 11.6 g of 1-iodo-3-hydroxy-4,4-trimethylene-1-trans-octene. Silylation of this material in the manner described above followed by distillation of the residual oil furnishes 13 g of pure product; bp 83°-84° C. (0.2 mm).

EXAMPLE 14 Preparation of 1-iodo-4,4-tetramethylene-3-trimethylsilyloxy-1-trans-octene

Treatment of 4,4-tetramethylene-3-trimethylsilyloxy-1-octyne (Example 10) in the manner described in Example 13 furnishes the subject product.

EXAMPLES 15-20

Treatment of the lithium salt of ethyl cyclobutanecarboxylate with the alkyl halides listed in Table 1 below by the procedure described in Example 1 furnishes the 2,2-trimethylene esters of the table.

                  TABLE 1                                                          ______________________________________                                         Ex.  Alkyl Halides                                                                             Product 2,2-Trimethylene esters                                ______________________________________                                         15   propyl iodide                                                                             ethyl 2,2-trimethylenepentanoate                               16   amyl iodide                                                                               ethyl 2,2-trimethyleneheptanoate                               17   hexyl iodide                                                                              ethyl 2,2-trimethyleneoctanoate                                18   benzyl iodide                                                                             ethyl 2,2-trimethylene-3-phenylpropionate                      19   2-cyclopen-                                                                               ethyl 2,2-trimethylene-4-cyclopentylbutyrate                        tyl-ethyl                                                                      bromide                                                                   20   1-chloro-2-                                                                               ethyl 2,2-trimethylene-4-hexynoate                                  butyne                                                                    ______________________________________                                    

EXAMPLES 21-27

Reduction of the various esters listed in Table 2 below with diisobutylaluminum hydride all in the manner described in Example 3 above is productive of the alcohols of the table.

                  TABLE 2                                                          ______________________________________                                                Starting Es-                                                                   ters of Ex-                                                             Example                                                                               ample      Product Alcohols                                             ______________________________________                                         21     15         2,2-trimethylenepentan-1-ol                                  22     16         2,2-trimethyleneheptan-1-ol                                  23     17         2,2-trimethyleneoctan-1-ol                                   24     18         2,2-trimethylene-3-phenylpropan-1-ol                         25     19         2,2-trimethylene-4-cyclopentylbutan-1-ol                     26     20         2,2-trimethylene-4-hexyn-1-ol                                27     55         2,2-trimethylene-4-cis-hexen-1-ol                            ______________________________________                                    

EXAMPLES 28-34

Oxidation of the alcohols listed in Table 3 below with chromium trioxide-pyridine complex by the procedure described in Example 5 above furnishes the corresponding aldehydes of the table.

                  TABLE 3                                                          ______________________________________                                              Starting Al-                                                                   cohols of Ex-                                                             Ex.  ample      Product 2,2-Trimethylenealdehydes                              ______________________________________                                         28   21         2,2-trimethylenevaleraldehyde                                  29   22         2,2-trimethyleneheptaldehyde                                   30   23         2,2-trimethyleneoctaldehyde                                    31   24         2,2-trimethylene-3-phenylpropionylaldehyde                     32   25         2,2-trimethylene-4-cyclopentylbutyraldehyde                    33   26         2,2-trimethylenehex-4-yn-1-al                                  34   27         2,2-trimethylene-4-cis-hexene-1-al                             ______________________________________                                    

EXAMPLES 35-41

Treatment of the various aldehydes listed below in Table 4 with lithium acetylide-ethylenediamine complex in the manner described in Example 7 furnishes the hydroxyacetylenes of the table.

                  TABLE 4                                                          ______________________________________                                              Starting al-                                                                   dehydes of                                                                Ex.  Example    Product Hydroxyacetylenes                                      ______________________________________                                         35   28         4,4-trimethylene-1-heptyn-3-ol                                 36   29         4,4-trimethylene-1-nonyn-3-ol                                  37   30         4,4-trimethylene-1-decyn-3-ol                                  38   31         4,4-trimethylene-5-phenyl-1-pentyn-3-ol                        39   32         4,4-trimethylene-6-cyclopentyl-1-hexyn-3-ol                    40   33         4,4-trimethylene-1,6-octadiyn-3-ol                             41   34         4,4-trimethylene-4-cis-hexene-3-ol                             ______________________________________                                    

EXAMPLES 42-48

Treatment of the various alcohols listed below in Table 5 with chlorotrimethylsilane in the manner described in Example 9 furnishes the corresponding trimethylsilyloxy acetylenes of the table.

                  TABLE 5                                                          ______________________________________                                              Starting                                                                       Alcohols                                                                  Ex.  of Example                                                                               Product Trimethylsilyloxyacetylenes                             ______________________________________                                         42   35        4,4-trimethylene-3-trimethylsilyloxy-1-heptyne                  43   36        4,4-trimethylene-3-trimethylsilyloxy-1-nonyne                   44   37        4,4-trimethylene-3-trimethylsilyloxy-1-decyne                   45   38        4,4-trimethylene-3-trimethylsilyloxy-5-phenyl-                                 1-pentyne                                                       46   39        4,4-trimethylene-3-trimethylsilyloxy-6-cyclo-                                  pentyl-1-hexyne                                                 47   40        4,4-trimethylene-3-trimethylsilyloxy-1,6-                                      octadiyne                                                       48   41        4,4-trimethylene-3-trimethylsilyloxy-4-cis-                                    octene-1-yne                                                    ______________________________________                                    

EXAMPLES 49-54

In the manner described in Example 13 treatment of the various acetylenes of Table 6 below with disiamylborane, made in situ from sodium borohydride and 2-methyl-2-butene, followed by oxidation of the so formed organoborane with trimethylamine oxide followed by treatment of this product with iodine and sodium hydroxide furnishes the trimethylsilyliodovinylcarbinols of the table.

                  TABLE 6                                                          ______________________________________                                              Starting                                                                       Acetylenes                                                                Ex.  of Example                                                                               Product Trimethylsilylvinylcarbinols                            ______________________________________                                         49   42        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                 trans-heptene                                                   50   43        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                 trans-nonene                                                    51   44        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                 trans-decene                                                    52   45        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-5-                                 phenyl-1-trans-pentene                                          53   46        1-loco-4,4-trimethylene-3-trimethylsilyloxy-6-                                 cyclopentyl-1-trans-hexene                                      54   47        1-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-                                 trans-octen-6-yne                                               ______________________________________                                    

EXAMPLE 55 Preparation of ethyl 2,2-trimethylene-4-cis-hexenoate

A solution of 5 g of ethyl 2,2-trimethylene-4-hexynoate (Example 20) in 40 ml of dry pyridine is hydrogenated in a Parr apparatus using 600 mg of 5% palladium on barium sulfate. After one hour when hydrogen uptake is complete, the solution is filtered through celite and the mother liquor is taken to dryness to furnish 4 g of product as an oil.

EXAMPLE 56 Preparation of 3-tetrahydropyranyloxy-1-propyne

To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-1-propyne and 260 g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooled to 0° C. in an ice bath, is added a solution of 20 mg of para-toluenesulfonic acid in 100 ml of methylene chloride, dropwise. The reaction mixture is stirred at 0° C. for one-half hour, and at ambient temperature for one hour. It is then poured into 200 ml of a 5% solution of sodium bicarbonate, the organic phase is separated, the aqueous phase extracted with 100 ml of methylene chloride, the combined organic phases washed with 100 ml of a solution of brine, dried over sodium sulfate, and evaporated under vacuum (12 mm) at 45° C. to give 300 g of crude product, which is purified by fractional distillation, bp 71°-73° C. (14 mm) to yield 250 g (89%) of a liguid.

EXAMPLE 57 Preparation of 3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne

To a stirred -20° C. solution of 125 g (0.89 mol.) of 3-tetrahydropyranyloxy-1-propyne (Example 56) in 450 ml of ether, under a nitrogen atmosphere, is added dropwise, over one hour, a solution of 45 ml (0.89 mol.) of 2.0 N n-butyllithium in hexane. After 150 ml of dry ether is added and the mixture stirred at -20° C. for 30 minutes, a solution of 98 g (0.89 mol.) of trimethylchlorosilane in 73 ml of ether is added dropwise. Stirring is continued for 30 minutes at -20° C. and at ambient temperature for 18 hours. The reaction mixture is again cooled to -20° C., and a solution of 90 ml of acetic acid in 300 ml of ether is added dropwise, followed by 90 ml of water. It is then diluted with 500 ml of water, and extracted 3 times with 300 ml of 5% sodium bicarbonate solution. The organic phase is separated, washed with 500 ml of a saturated brine solution, dried over sodium sulfate, and evaporated at 40° C. under vacuum (12 mm.). The curde product is fractionally distilled, bp 120°-125° C. (18 mm.), to yield 120 g of an oil.

EXAMPLE 58 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne

To a stirred -78° C. solution of 62 ml (124 mmol.) of a 2.0 M solution of n-butyllithium in hexane and 50 ml of dry tetrahydrofuran, under a nitrogen atmosphere is added dropwise, a solution of 24 g (113 mmol.) of 3-tetrahydropyranyloxy-1-trimethylsilyl-1-propyne (Example 57) in 35 ml of tetrahydrofuran. This red solution is stirred one hour at -78° C., then a freshly prepared solution of zinc iodide (135 mmol.) in 125 ml of tetrahydrofuran [F. Mercier, R. Epsztein, and S. Holand, Bull. Soc. Chim. France, 2, 690 (1972)] is added dropwise at -78° C. until the mixture turns yellow. After stirring an additional hour at -78° C., a solution of 21 g (250 mmol.) of n-valeraldehyde in 35 ml of tetrahydrofuran is added dropwise and the reaction mixture stirred for one hour at -78° C. and 18 hours at ambient temperature. It is then cooled to 0° C. and a solution of 12 ml of acetic acid in 65 ml of ether is added dropwise, followed by 75 ml of ice-water. The phases are separated and the aqueous phase is extracted twice with ether. The combined organic phases are washed 3 times with saturated sodium bicarbonate solution, until the last wash is basic, then with a saturated brine solution, dried over sodium sulfate, and evaporated to give 40 g of yellow oil. The crude product may be purified on a 4"×40" dry column of alumina, and eluted with chloroform. I.R.: neat; 3550 (OH), 2200 (C═C), 840, 750 [(CH₃)₃ Si], cm⁻¹

EXAMPLE 59 Preparationn of d,l-erythro-3,4-dihydroxy-1-trimethylsilyl-1-octyne

A soolution of 19.6 g (0.066 mol) of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne (Example 58) in 55.5 ml of ethanol, 22.2 ml of acetic acid, and 22.2 ml of water is heated at reflux for 3 hours. The cooled mixture is taken to dryness and evaporated twice with benzzene. The residue is taken up in hexane, washed 3 times with saturated potassium bicarbonate solution, dried with magnesium sulfate, and evaporated-to give 17.0 g of crude product. IR: neat, 3500-3400, broad (two OH)

EXAMPLE 60 Preparation of d,l-erythro-3,4-isopropylidenedioxy-1-trimethylsilyll-1-octyne

To a stirred solution of 17.0 g (79.5 mmol.) of crude d,l-erythro-15,16-dihydroxy-1-trimethylsilyl-1-octyne (Example 59) is 33.6 ml of 2,2-dimethoxy propane at 0° C., is added 0.05 ml of 60% perchloric acid. After 30 minutes at ambient temperature, the mixture is shaken with 50 ml of hexane and 25 ml of saturated sodium bicarbonate solution. The hexane phase is separated, dried with magnesium sulfate, and evaporated to give 19.0 g of crude product. 2.13 g of iodine in 53 ml of tetrahydrofuran into 766 ml of a 0° C. 15% solution of sodium hydroxide in water and the whole stirred vigorously at 0° C. for 45 minutes. The organic phase is separated, the aqueous phase is extracted twice with ether, the combined organic phases are washed with a 5% solution of sodium thiosulfate, dried with magnesium sulfate, and evaporated. The crude product is chromatographed on a dry column of silica gel, by eluting with chloroform, to yield 1.2 g (25%) of a yellow oil.

IR: neat; 1599 sharp, 945 ##STR37## cm⁻¹.

EXAMPLE 63 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A solution of 3.0 g (13.2 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne is heated at 100° C. for 15 hours with 3 ml of acetic anhydride and 10 ml of pyridine. The mixture is evaporated to dryness, dissolved in ether, washed with sodium bicarbonate solution and water. The organic phase is dried over magnesium sulfate and evaporated to give 2.5 g of the subject compound as an oil. IR: neat; 2200 (C C), 1730 (C═O), 830, 760 [(CH₃)₃ Si], cm⁻¹.

EXAMPLE 64 Preparation of d,l-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

In the manner of Example 59, 2.5 g (7.4 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 63) in a solution of ethanol, acetic acid, and water is heated at 100° C. for 3 hours. A ter workup, the crude product is chromatographed on a 7/8"×22" dry column of silica gel, and eluted with chloroform to give 1.0 g of a yellow oil.

IR: neat; 3500 (OH), 1730 (C═O), cm⁻¹.

EXAMPLE 61 Preparation of d,l-erythro-3,4-isopropylidenedioxy-1-octyne

A mixture of 19.0 g (75.0 mmol.) of crude d,l-erythro-3,4-isopropylidenedioxy-1-trimethylsilyl-1-octyne (Example 60) with 95 ml of methanol and 3.0 g of potassium carbonate is refluxed for one hour. The mixture is cooled and evaporated at 50° C. (13 mm), taken up in 250 ml of benzene, and washed with 100 ml of water. The water is saturated with salt, the organic phase separated, dried with magnesium sulfate, and evaporated to give 12 g of crude product. Fractional distillation yields 7.0 g of the subject compound as a colorless oil, bp 103°-106° C. (13 mm).

IR: neat; 3300 sharp (H--C═C), 2100, (C.tbd.C), 780 (erythro configuration) cm⁻¹

nmr: δ CDCl₃ ; TMS; 4.75 (dd., l, C.tbd.C--CH--CH, J=2 Hz, J═5 Hz), 4.10 (m, l, C.tbd.C--CH--CH--CH₂, 2.5 (d, l, H--C C--CH), 1.9-1.2 (m, 14, alkyl), 0.90 (m, 3H, CH₂ CH₃).

EXAMPLE 62 Preparation of d,l-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-octene

To a stirred 0° C. slurry of 0.852 g (0.023 mol.) of sodium borohydride and 4.21 g (0.060 mol.) of 2-methyl-2-butene in 40 ml of dry tetrahydrofuran, under an argon atmosphere, is added dropwise 4.26 g (0.030 mol.) of boron trifluoride etherate complex. A solution of 2.73 g (0.015 mol.) of d,l-erythro-3,4-isopropylidenedioxy-1-octyne (Example 61) in 5 ml of tetrahydrofuran is added dropwise, the ice bath removed, and the mixture allowed to stir at ambient temperature for two hours. It is then cooled again to 0° C., and 2.88 g (0.105 mol.) of dry trimethylamine oxide is added in portions over 30 minutes. After stirring 3 hours at room temperature, this mixture is poured simultaneously with a 0° C. solution of

EXAMPLE 65 Preparation of d,l-erythro-3-paratoluenesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne

To a solution of 7.5 g (41.0 mmol.) of d,l-erythro-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 64) in 41 ml of dry pyridine is added 11.0 g (58 mmol.) of para-toluenesulfonyl chloride and the resulting solution is stirred at 25° C. for 15 hours. The mixture is then warmed at 40° C. for one hour, and after cooling, partitioned between 500 ml of diethyl ether and 100 ml of 1.0 N hydrochloric acid. The organic phase is washed three times with 100 ml of 1.0 N hydrochloric acid, once with dilute sodium bicarbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil. The crude product is purified on a 2"×24" dry column of silica gel, and eluted with chloroform to yield a yellow oil.

IR: neat; 1730 (C═O), 1595 (aromatic) cm⁻¹.

EXAMPLE 66 Preparation of d,l-threo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne

A mixture of 15.5 g (39.0 mmol.) of d,l-erythro-3-para-toluennesulfonyloxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 65), 5.0 g of calcium carbonate, 25 ml of water and 250 ml of tetrahydrofuran is refluxed with stirring for 4 days. The mixture is cooled, 100 ml of water added and the organic phase separated. The aqueous phase is extracted with ether, the combined organic phases dried with magnesium sulfate, and evaporated. The crude product is chromatographed on a 3"×30" dry column of silica gel, and eluted with chloroform to give 7.0 g of an oil.

IR:: neat; 3500, (OH), cm⁻¹.

EXAMPLE 67 Preparation of d,l-threo-3,4-dihydroxy-1-octyne

A solution of 7.0 g (28 mmol.) of d,l-threo-3-hydroxy-4-acetyloxy-1-trimethylsilyl-1-octyne (Example 66) in 50 ml of methanol is stirred at room temperature for 24 hours with a solution of 6.3 g (112 mmol.) of potassium hydroxide in 50 ml of water. The mixture is extracted twice with hexane, washed with 0.5 M hydrochloric acid, brine, and dried with magnesium sulfate. After evaporation, the subject compound is obtained as a yellow oil.

IR: neat, 2500 broad (2-OH), cm⁻¹.

EXAMPLE 68 Preparation of d,l-threo-3,4-isopropylidenedioxy-1-octyne

In the manner of Example 60, treatment of a solution of d,l-threo-3,4-dihydroxy-1-octyne (Example 67) in dimethoxypropane with 60% perchloric acid, and fractional distillation (12 mm) is productive of the subject compound as a colorless oil, containing 15% of d,l-erythro-3,4-isopropylidenedioxy-1-octyne (Example 60), as an impurity.

IR: neat; 810 (threo configuration).

nmr: δ CDCl₃ ; TMS; 4.2 (dd, l, --C.tbd.C--CH--, J's--2H_(z), 6H_(z)), 4.1-3.9 (m, l, --C.tbd.C--CH--CH--CH₂ --), 2.5 (d, l, H--C.tbd.C--, J═2H_(z)), 1.9-1.2 (m, 14, alkyl), 0.90 (m, 3H, CH₂ --CH₃).

EXAMPLE 69 Preparation of d,l-threo-1-iodo-3,4-isopropylidenedioxy-trans-1-octene

In the manner of Example 62, d,l-threo-3,4-isopropylidenedioxy-trans-1-octyne (Example 68) is treated successively with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide to give the subject compound.

EXAMPLE 70 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne

Alkaline hydrolysis of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-1-octyne (Example 58) by the procedure of Example 61 is productive of the subject compound.

EXAMPLE 71 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne

To a stirred slurry of 6.0 g (150 mmol.) of a 60% oil dispersion of sodium hydride and 96 g of iodomethane, under an argon atmosphere, is added 700 ml of dry tetrahydrofuran. The stirred mixture is cooled to -20° C. and a solution of 30 g (133 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne (Example 70), is added dropwise, followed by 0.1 ml of methanol. The mixture is stirred at ambient temperature for 24 hours, 10 ml of methanol is added, and evaporated. The residue is taken up in ether, washed 3 times with water, dried over magnesium sulfate, and evaporated. The crude product is purified by fractional distillation to yield 16.3 g of a colorless oil, bp 137°-140° C. (12 mm).

EXAMPLE 72 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-1-octen

In the manner of Example 62, 1.20 g (5.0 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-octyne (Example 71) is treated successively with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide. Chromatography on a 2"×36" dry column of silica gel and elution with chloroform is productive of 0.80 g (40%) of the subject compound as an oil.

nmr: δ^(CDCl).sbsp.3_(TMS) ; 7.9-6.1 (m, 2, HC═CH), 4.9-4.6 (2 m, 2, c═C--CH, O--CH--O), 4.3-4.0 (m, 1, c═c--CH--CH--CH₂), 3.9-3.0 (m, 6, CH₂ --O--CH, OCH₃), 1.8-1.2 (m, 12H, alkyl), 0.9 (m, 3, --CH₃).

EXAMPLE 73 Preparation of d,l-erythro-3-hydroxy-4-methoxy-1-iodo-trans-1-octene

A solution of 3.10 g (8.24 mmol.) of d,l-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-1-octene (Example 72) in 60 ml of acetic acid, 30 ml of tetrahydrofuran, and 15 ml of water is stirred at ambient temperature for 18 hours. It is then evaporated at 70° C. under high vacuum (1.0 mm), and three times with 40 ml of toluene to give the crude product as an oil.

EXAMPLE 74 Preparation of d,l-erythro-3-trimethylsilyloxy-4-methoxy-1-iodo-trans-1-octene

To a stirred solution of 3.0 g (10.2 mmol.) of d,l-erythro-3-hydroxy-4-methoxy-1-iodo-trans-1-octene (Example 73) in 11.0 ml of dry dimethylformamide and 1.90 g (28.0 mmol.) of imidazole cooled to 0° C. is added, dropwise, 1.35 g (12.5 mmol.) of trimethylsilyl chloride. The reaction mixture is stirred a further 4 hours at room temperature. It is then poured into a mixture of 100 ml of hexane and 25 ml of water, the organic phase is separated, washed twice with water, once with a solution of saturated sodium chloride, dried over magnesium sulfate, and evaporated. The crude product is purified by fractional distillation to yield 2.0 g of a colorless oil, bp 82°-83° C. (0.3 mm).

IR: neat; 1602 sharp ##STR38## 840, 750 broad [(CH₃)₃ Si--], cm⁻¹.

EXAMPLE 75 Preparation of d,l-erythro-1-iodo-3,4-dihydroxy-trans-1-octene

A solution of 1.40 g (4.50 mmol.) of d,l-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-octene (Example 62) in 30 ml of acetic acid, 10 ml of tetrahydrofuran and 10 ml of water is stirred and heated at 50° C. for five hours. It is then evaporated at 40° C. under high vacuum (1.0 mm), and twice more with 50 ml of benzene. Crystallization from 10 ml of chloroform at 0° C. is productive of 700 mg of the white crystalline subject product.

EXAMPLE 76 Preparation of d,l-erythro-1-iodo-3,4-bis-trimethylsilyloxy-trans-1-octene

To a stirred solution of 700 mg (2.40 mmol.) of d,l-erythro-1-iodo-3,4-dihydroxy-trans-1-octene (Example 75) and 800 mg (12.0 mmol.) of imidazole, in 10 ml of dry dimethylformamide at 0° C. is added dropwise 1.20 g (11.0 mmol.) of trimethylchlorosilane. The ice bath is removed, and the mixture is stirred and heated at 50° C. for five hours. It is then cooled, shaken with 50 ml of hexane and 50 ml of water, the organic layer separated and washed with 15 ml of 0.5 M hydrochloric acid, 15 ml of a saturated solution of sodium bicarbonate, dried with magnesium sulfate, and evaporated. This crude product is fractionally distilled, bp 90°-92° C. (0.40 mm) to yield 250 mg of a colorless oil.

EXAMPLE 77 Preparation of d,l-erythro-3-trimethylsilyloxy-4-ethoxy-1-iodo-tranns-1-octene

Following the procedure of Example 71, ethylation using iodoethane of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne for a period of 22 hours is productive of the corresponding d,l-erythro-3-tetrahydropyranyloxy-4-ethoxy-1-octyne. This intermediate is converted to d,l-erthyro-3-tetrahydropyranyloxy-4-ethoxy-1-iodo-trans-1-octene when treated successively with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide solution after the procedure of Example 72. Acid hydrolysis by the method of Example 18 to d,l-erythro-3-hydroxy-4-ethoxy-1-iodo-trans-1-octene, followed by treatment with chlortrimethylsilane and imidazole in dimethylformamide using the procedure of Example 74, and subsequent distillation, is productive of the subject compound.

EXAMPLES 78-82

By the method of Example 58 reaction of 1-trimethylsilyl-3-tetrahydropyranyloxy-1-propyne with n-butyllithium and subsequent treatment with the aldehydes listed in Table 7, below, provides the d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkynes of the table.

                                      TABLE 7                                      __________________________________________________________________________                    Product d,1-erythro-3-tetrahydropyranyloxy-                     Example                                                                             Starting Aldehyde                                                                        4-hydroxy-1-trimethylsilyl-1-alkyne                             __________________________________________________________________________     78   n-buanal  d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-1-heptyne                                               79   n-hexanal d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-1-nonyne                                                80   n-heptanal                                                                               d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-1-decyne                                                81   4-methyl-n-pentanal                                                                      d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-7-methyl-1-octyne                                       82   2-trans-n-pentenal                                                                       d,1-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-                         hydroxy-5-trans-en                                              __________________________________________________________________________

EXAMPLES 83-87

Hydrolysis of the 3-tetrahydropyranyloxy group of the d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkynes listed in Table 8 below by the method described in Example 59, followed by conversion of the resulting d,l-erythro-1-trimethylsilyl-3,4-dihydroxy-1-alkyne to the corresponding d,l-erythro-1-trimethylsilyl-3,4-isopropylidenedioxy-1-alkyne by treatment with dimethoxypropane in the presence of perchloric acid by the method described in Example 60, followed by desilylation to the corresponding d,l-erythro-3,4-isopropylidenedioxy-1-alkyne by the procedure of Example 61 followed by treatment with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide solution by the method described in Example 62 provides the product d,l-erythro-1-iodo-3,4-isopropylidenedioxy-trans-1-alkenes of Table 8, below.

                  TABLE 8                                                          ______________________________________                                              Starting d,1-erythro-                                                          1-trimethylsilyl-3-                                                            tetrahydropyranloxy-                                                           4-hydroxy-1-alkyne of                                                                         Product d,1-erythro-1-iodo-3,4-iso-                        Ex.  Example        propylidenedioxy-trans-1-alkene                            ______________________________________                                         83   78             d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-trans-1-heptene                                  84   79             d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-trans-1-nonene                                   85   80             d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-trans-1-decene                                   86   81             d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-7-methyl-trans-1-octene                          87   82             d,1-erythro-1-iodo-3,4-isopropyli-                                             denedioxy-trans,trans-1,5-octadiene                        ______________________________________                                    

EXAMPLES 88-92

Acetylation of the 4-hydroxy group of the d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-1-alkynes listed in Table 9 below by the method described in Example 63, followed by hydrolysis of the resulting d,l-erythro-1-trimethylsilyl-3-tetrahydropyranyloxy-4-acetyloxy-1-alkynes to the corresponding d,l-erythro-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by the method of Example 65, followed by epimerization to d,l-threo-1-trimethylsilyl-3-hydroxy-4-acetyloxy-1-alkynes by the method of Example 66 followed by hydrolysis by the method of Example 67 to give d,l-threo-3,4-dihydroxy-1-alkynes are converted to the corresponding d,l-threo-3,4-isopropylidenedioxy-1-alkynes by treatment with dimethoxypropane in the presence of perchloric acid by the method described in Example 68 followed by treatment with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide solution by the method described in Example 62 provides the product d,l-threo-3,4-isopropylidenedioxy-trans-1-alkenes of Table 9 below.

                                      TABLE 9                                      __________________________________________________________________________          Starting d,1-erythro-1-trimethyl-                                              silyl-3-tetrahydropyranyloxy-1-                                                                Product d,1-threo-1-iodo-3,4-iso-                         Example                                                                             hydroxy-1-alkyne of Example                                                                    propylidenedioxy-trans-1-alkene                           __________________________________________________________________________     98   78              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1-heptene                                           89   79              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1-nonene                                            90   80              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1-decene                                            91   81              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1,7-methyl-1-octene                                 92   82              d,1-threo-1-iodo-3,4-isopropylidenedioxy-                                      trans-1,5-trans-1-octadiene                               __________________________________________________________________________

EXAMPLE 93 Preparation of 1-octyn-4-ol

A suspension of 24.3 g (1.0 mole) of magnesium in 90 ml of dry ether is stirred at room temperature under nitrogen with 100 mg of mercuric chloride. The reaction is initiated by the addition of 2 ml of propargyl bromide and maintained by the dropwise addition of a solution of 119.5 g (1.0 mmole) of propargyl bromide and 107.7 g (1.25 mole) of valenaldehyde in 300 ml of dry ether. While the initial reaction is quite vigorous and is maintained at 30° C. only by cooling in an ice bath it may become necessary to heat the mixture to reflux temperature after about a third of the ether solution is added in order to maintain the reaction. After the addition is complete the reaction mixture is refluxed until most of the magnesium is dissolved (several hours) and the reaction mixture is decanted from excess magnesium into 1500 ml of stirred ice-cold ammonium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml portions of ether. The combined ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Evaporation of the ether under vacuum leaves about 115 g of yellow oil, which is distilled through a 15 cm Vigreaux column at 18 mm. The fraction boiling at 81°-82° C. is collected (36 g) and the higher-boiling and lower-boiling distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a trace of allene (5.1μ) and gas-liquid partition chromatography shows a purity of about 98% for the main fraction.

EXAMPLES 94-97

The product 1-alkyn-4-ols of Table 10 below are prepared by treatment of the aldehydes listed in Table 10 with propargyl magnesium bromide by the procedure described above in Example 93.

                  TABLE 10                                                         ______________________________________                                                                    Product                                             Example    Starting Aldehyde                                                                              1-alkyn-4-ol                                        ______________________________________                                         94         n-hexaldehyde 1-nonyn-4-ol                                          95         n-heptaldehyde                                                                               1-decyn-4-ol                                          96         n-butyraldehyde                                                                              1-heptyn-4-ol                                         97         3-cis-hexenaldehyde*                                                                         4-hydroxy-6-cis-                                                               ene-1-nonyne                                          ______________________________________                                          *M. Winter, Helv. Chim. Acta, 46, 1792 (1963).                           

EXAMPLE 98 Preparation of 4-triphenylmethoxy-1-octyne

A mixture of 10 g (0.08 moles) of 4-hydroxy-1-octyne [L. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 (1957), also Example 93] and 30.75 g (0.09 moles) of triphenylmethyl bromide in 85 ml of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed successively with ice cold 2% hydrochloric acid, saturated sodium chloride solution, dried with magnesium sulfate, and taken to dryness. Column chromatography of the residue on Florisil affords an oil; λ max 3.01, 4.72 (acetylenic hydrogen), 6.28, 9.65 and 14.25μ (triphenylmethoxy group).

EXAMPLE 99 Preparation of 4-triphenylmethoxy-1-hexyne

A stirred solution of 9.81 g (0.10 moles) of 4-hydroxy-1-hexyne and 33.5 g (0.12 moles) of triphenylmethyl chloride in 100 ml of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, max. 3290 (acetylenic hydrogen), 1600, 1030 and 705 cm⁻¹ (triphenylmethoxy group).

EXAMPLES 100-106

The triphenylmethoxy substituted 1-alkynes listed in Table 11 below are prepared by the method of Example 98 from triphenylmethyl bromide and the corresponding hydroxy substituted 1-alkynes, appropriate literature references to which are provided in the table.

                  TABLE 11                                                         ______________________________________                                              Reference to Starting                                                                             Product Triphenylmethoxy                               Ex.  Hydroxy Substituted 1-Alkyne                                                                      Substituted 1-Alkyne                                   ______________________________________                                         100  Reference 1        4-triphenylmethoxy-                                                            1-pentyne                                              101  Reference 1        4-triphenylmethoxy-                                         (Example 96)       1-heptyne                                              102  Reference 1        4-triphenylmethoxy-                                                            5-methyl-1-hexyne                                      103  Reference 2        4-triphenylmethoxy-                                         (Example 94)       1-nonyne                                               104  Reference 3        4-triphenylmethoxy-                                         (Example 95)       1-decyne                                               105  Reference 4        4-triphenylmethoxy-                                                            5-ethyl-1-heptyne                                      106  Example 97         4-triphenylmethoxy-                                                            6-cis-ene-1-nonyne                                     ______________________________________                                          References:                                                                    1. G. Fontaine, et al., Bull. Soc. Chem. France, 1447 (1963).                  2. S Abe and K. Sato, Bull. Soc. Chem. Japan, 29, 88 (1956); Chem. Abstr.      50, 13737 (1956).                                                              3. L. Crombie and A. G. Jacklin, J. Chem. Soc., 1622 (1957);                   4. Nobuharra, Akio, Chem. Abstr., 70, 3219 (1969).                       

EXAMPLE 107 Preparation of 1-iodo-4-triphenylmethoxy-trans-1-octene

To a stirred suspension of 1.78 g (0.074 mole) of sodium borohydriide in 200 ml of dry glyme at -5° C. under nitrogen is added 15.8 g (0.22 mole) of 2-methyl-2-butene and 16.2 g (0.11 mole) of boron trifluoride etherate, and the mixture is stirred for 2 hours at -5° C. to 0° C. A solution of 37.5 g (0.10 mole) of 4-trityloxy-1-octyne (Example 98) in 50 ml of glyme is added to the cold solution during 5-10 minutes, and the solution is allowed to warm to 20° C. during 1.5 hours. The reaction mixture is cooled to 0° C. and 30 g (0.4 mole) of dry trimethylamine-N-oxide is added during 5 minutes. On removing the cooling bath the temperature rises to 40° C. and the mixture is kept between 30°-40° C. for 1.5 hours. The suspension is poured rapidly into one liter of ice cold 15% sodium hydroxide solution during good stirring and a solution of 80 g of iodine in 200 ml of tetrahydrofuran is added immediately. Stirring is continued for 30 minutes without further cooling and the organic layer is separated. The aqueous layer is extracted with three 200 ml portions of ether and the combined organic layers are washed successively with water, 5% sodium thiosulfate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to yield 50 g of yellow oil. The bulk of the oil is dissolved in hexane and, after decantation from a gummy solid the hexane solution is percolated through a 5.1 cm diameter column of 1500 g of alumina with additional hexane. Fractions containing the desired product are concentrated to a pale yellow oil (33 g) which has n.m.r. and infrared spectra characteristics of the desired product.

EXAMPLES 108-115

Treatment of the triphenylmethoxy substituted 1-alkynes listed in Table 12 below with disiamylborane, prepared in situ from 2-methyl-2-butene, boron, trifluoride and sodium borohydride, followed by trimethylamine N-oxide, and then sodium hydroxide and iodine - all by the procedure described in Example 107 above furnsihes the product triphenylmethoxy substituted 1-iodo-1-trans-alkenes of the table.

                  TABLE 12                                                         ______________________________________                                                  Starting Triphenyl-                                                                            Product 1-Iodo-tri-                                            methoxy Substituted                                                                            phenylmethoxysubsti-                                  Example  1-Alkyne of Example                                                                            tuted-1-traans-alkene                                 ______________________________________                                         108       99             1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               hexene                                                109      100             1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               pentene                                               110      101             1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               heptene                                               111      102             1-iodo-4-triphenyl-                                                            methoxy-5-methyl-1-                                                            trans-hexene                                          112      103             1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               nonene                                                113      104             1-iodo-4-triphenyl-                                                            methoxy-1-trans-                                                               decene                                                114      106             1-iodo-4-triphenyl-                                                            methoxy-1-trans-6-                                                             cis-nonadiene                                         ______________________________________                                    

EXAMPLES 116-124

The starting aldehydes or ketones of Table 13 below are converted to the product 1-alkyn-4-ols of the table by the procedure described in Example 93.

                  TABLE 13                                                         ______________________________________                                              Starting Aldehyde or                                                      Ex.  Ketone          Product 1-Alkyn-4-ol                                      ______________________________________                                         115  2-octanone      4-methyl-4-hydroxy-1-decyne                               116  trans-2-hexenal 4-hydroxy-5-trans-nonen-1-yne                             117  2,2-dimethylhexanal                                                                            5,5-dimethyl-4-hydroxy-1-nonyne                           118  2-heptanone     4-methyl-4-hydroxy-1-nonyne                               119  2,2-dimethylpentanal                                                                           5,5-dimethyl-4-hydroxy-1-octyne                           120  2-methylpentanal                                                                               5-methyl-4-hydroxy-1-octyne                               121  2-methylhexanal 5-methyl-4-hydroxy-1-nonyne                               122  2-hexanone      4-hydroxy-4-methyl-1-octyne                               123  trans-3-hexen-2-one.sup.a                                                                      4-hydroxy-4-methyl-5-trans-                                                    octen-1-yne                                               124  trans-2-pentenal.sup.b                                                                         4-hydroxy-5-trans-octen-1-yne                              124a                                                                               trans-2-heptenal.sup.b                                                                         4-hydroxy-5-trans-decen-1-yne                             ______________________________________                                          .sup.a G. Sturtz, Bull. Soc. Chim. Fr., 1967, 2477.                            .sup.b R. I. Hoaglin and D. M. Hirsh, U.S. Pat. No. 2,628,257; Chem.           Abstr., 48, 1423e (1954).                                                

EXAMPLE 125 Preparation of 4-methyl-4-trimethylsilyloxy-1-octyne

To a stirred solution of 75.4 g (0.537 moles) of 4-hydroxy-4-methyl-1-octyne (Example 122), 104.9 g (1.54 moles) of imidazole, and 325 ml of dimethylformamide is added 65.2 g (0.60 moles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 800 ml of hexane. The mixture is washed thoroughly with water followed by sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate, filtered, and evaporated to give a liquid, p.m.r. spectrum, δ 1.26 (singlet, 3, CH₃), 1.92 (triplet, 1, HC), 2.30 (doublet, 2, CH₂).

EXAMPLES 126-129

The 1-alkyn-4-ols of Table 14 are converted to the product trimethylsilyl ethers of the table by treatment with chlorotrimethylsilane according to the procedure described in Example 125.

                                      TABLE 14                                     __________________________________________________________________________     Example                                                                             Starting 1-Alkyn-4-ol                                                                        Product Trimethylsilyl Ether                                __________________________________________________________________________     126  5,5-dimethyl-4-hydroxy-1-                                                                    5,5-dimethyl-4-trimethylsilyloxy-1-nonyne                        nonyne (Ex. 117)                                                          127  4-methyl-4-hydroxy-1-nonyne                                                                  4-methyl-4-trimethylsilyloxy-1-nonyne                            (Ex. 118)                                                                 128  5,5-dimethyl-4-hydroxy-1-                                                                    5,5-dimethyl-4-trimethylsilyloxy-1-octyne                        octyne (Ex. 119)                                                          129  4-hydroxy-4-methyl-5-trans-                                                                  4-methyl-4-trimethylsilyloxy-5-trans-                            octen-1-yne (Ex. 123)                                                                        octen-1-yne                                                  129a                                                                               4-hydroxy-4-methyl-1-decyne                                                                  4-methyl-4-trimethylsilyloxy-1-decyne                            (Ex. 124a)                                                                __________________________________________________________________________

EXAMPLE 130 Preparation of 1-iodo-4-hydroxy-4-methyl-trans-1-octene

To a stirred solution of 400 ml of 0.5 M bis-(3-methyl-2-butyl)borane in glyme, prepared from sodium borohydride, 2-methyl-2-butene, and boronitrifluoride etherate as in Example 107, is added 63.7 g (0.30 moles) of 4-methyl-4-trimethylsilyloxy-1-octyne (Example 125) at -10° C. The solution is stirred at ambient temperature for 2.5 hours, cooled to -10° C., and treated during 30 minutes with 158 g (2.1 moles) of solid trimethylamine oxide with cooling. The mixture is stirred at ambient temperature for 2 hours and then poured into a stirred, ice-cold solution of 15% aqueous sodium hydroxide; the stirred mixture is treated immediately with a solution of 426 g (1.68 moles) of iodine in 1100 ml of tetrahydrofuran. After 4 hours the mixture is extracted with ether. The extract is washed successively with water, aqueous sodium thiosulfate, and brine and dried over magnesium sulfate. The extract is concentrated, and the residue is subjected to chromatography on silica gel with hexane to provide an oil, p.m.r. (CDCl₃); δ 1.18 (singlet, 4-CH₃ group).

EXAMPLES 131-134

The 4-trimethylsilyloxy-1-alkynes of Table 15 are converted to the 4-hydroxy-1-iodo-trans-1-octenes of the table by the procedure described in Example 130.

                  TABLE 15                                                         ______________________________________                                                  Starting 4-Tri-                                                                methylsilyloxy-                                                                1-octyne of  Product 4-Hydroxy-1-iodo-                                Example  Example      trans-1-octene                                           ______________________________________                                         131      126          1-iodo-5,5-dimethyl-4-hy-                                                      droxy-trans-1-nonene                                     132      127          1-iodo-4-methyl-4-hydroxy-                                                     trans-1-nonene                                           133      128          1-iodo-5,5-dimethyl-4-hy-                                                      droxy-trans-1-octene                                     134      129          1-iodo-4-methyl-4-hydroxy-                                                     trans,trans-1,5-octadiene                                 134a     129a        1-iodo-4-methyl-4-hydroxy-                                                     trans-1-decene                                           ______________________________________                                    

EXAMPLE 135 Preparation of 1-iodo-4-methyl-4-trimethylsilyloxy-trans-1-octene

To a stirred mixture of 24.5 g (55.6 mmoles) of 1-iodo-4-hydroxy-4-methyl-trans-1-octene (Example 130), 13.6 g (200 mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g (100 mmoles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 250 ml of hexane. The mixture is washed thoroughly with water followed by brine and dried over magnesium sulfate. After removal of the solvent, the product is distilled to give a colorless liquid, bp 67.5°-68° C. (0.07 mm).

EXAMPLES 136-139

The 1-iodo-4-hydroxy-trans-1-alkenes of Table 16 are converted to the product trimethylsilyl ethers of the table according to the procedure described in Example 135.

                  TABLE 16                                                         ______________________________________                                                  Starting 1-Iodo-4-                                                             hydroxy-trans-1-                                                                              Product Trimethylsilyl                                 Example  alkene of Example                                                                             Ether                                                  ______________________________________                                         136      131            1-iodo-5,5-dimethyl-4-                                                         trimethylsilyloxy-                                                             trans-1-nonene                                         137      132            1-iodo-r-methyl-4-tri-                                                         methylsilyloxy-trans-1-                                                        nonene                                                 138      133            1-iodo-5,5-dimethyl-4-                                                         trimethylsilyloxy-                                                             trans-1-octene                                         139      134            1-iodo-4-methyl-4-tri-                                                         methylsilyloxy-trans,-                                                         trans-1,5-octadiene                                     139a     134a          1-iodo-4-methyl-4-tri-                                                         methylsilyloxy-trans-1-                                                        decene                                                  139b     134b          1-iodo-4-methyl-4-tri-                                                         methylsilyloxy-trans-1-                                                        decene                                                 ______________________________________                                    

EXAMPLE 140 Preparation of 4-benzoyloxy-1-octyne

To a stirred solution of 63. g (0.50 moles) of 1-octyn-4-ol (Example 93) in 500 ml of pyridine is added 77 g (0.55 moles) of beazoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue in ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, λ max. 3240 (terminal acetylene) and 1730 cm⁻¹ (benzyloxy group).

EXAMPLE 141 Stereoselective Hydrolysis of Racemic 4-benzoyloxy-1-octyne by Rhizopus arrhizus

An agar slant of R. arrhizus (MUMF 1638) is used to inoculate 7 shake flasks (250 ml Erlenmeyer). Each flask contains 50 ml of a medium consisting of 2% Edamine, 2% glucose, and 0.72% corn steep liquor in water with pH adjusted to 7.0. A total of 14 such flasks are incubated on a rotary shaker at 28° C. After 72 hours incubation, 50 mg of racemic 4-benzoyloxy-1-octyne (Example 135) in 0.1 ml of acetone is added to each flask. After 28 hours the flasks are harvested and worked up by extraction of the whole mash with an equal volume of chloroform. The combined extracts are dried over magnesium sulfate and concentrated. The resulting oil is chromatographed on a column of silica gel with hexane progressively enriched in ethyl acetate.

From fractions 3-6 is obtained 150 mg of colorless oil, identical to 4-benzoyloxy-1-octyne, [α]_(D) ²⁵ =5±1.0° (C=0.91, ethyl acetate). This compound has the (S)-configuration.

From fractions 13-20 is obtained 75 mg of colorless oil, identical to 4-hydroxy-1-octyne, [α]_(D) ²⁵ =-17±1.0° (C=0.77, ethyl acetate). This compound has the (R)-configuration.

The strain of R. arrhizus utilized in this experiment is a higher fungus which grows steadily on a variety of artificial media at 20°-25° C. In this study of the taxonomic aspects of the culture, Petri dishes of potato-dextrose, malt extract, and cornmeal agars were inoculated and incubated at ambient room temperature for 10 days. Observations of cultural and morphological characteristics are recorded in the description below:

Colonies on Petri dishes of potato-dextrose agar growing rapidly, covering the agar surface in 3-5 days and producing a thick, loose mat of grayish mycelium. Colony surface characterized by abundant black sporangia. Colony reverse grayish white. Colonies on malt extract agar growing rapidly, covering the agar surface in 3-5 days. Mycelial mat thick, grayish-yellow. Colony surface becoming brownish-black from masses of sporangia. Colony reverse yellowish. Colonies on cornmeal agar very thin, whitish; spreading across agar surface. Cultures transparent with relatively few sporangia produced. Visibility of micromorphology is good on this medium. Rhizoids produced sparingly along stoloniferous hyphae. Generally two to three sporangiophores arose from rhizoids. Walls of sproangiophores olive brown, 14.0-20.0 μm in width at base, tapering slightly to apex; 0.5-1.5 mm in length. Sporangiophores terminated by spherical sporangia, 130-225 μm in diameter. Columellae hemispherical, 3-50 μm high by 50-70 μm wide. Spores brownish when mature, 6.0-8.5 μm×4.5-6.0 μm. Spore walls conspicuously marked by longitudinal striations.

EXAMPLE 142 Preparation of (S)- 4-hydroxy-1-octyne

A solution of 1.15 g (5.0 mmoles) of (S)-4-benzoyloxy-1-octyne (Example 141) and 1.40 g (25 mmoles) of potassium hydroxide in 50 ml of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-1-octyne [α]_(D) ²⁵ =+17+1.0° (C=0.77, ethyl acetate). This compound has the (S)-configuration.

EXAMPLES 143-148

The starting 1-alkyn-4-ols of Table 17 below are converted to the triphenylmethoxy substituted 1-alkynes by the method of Example 98.

                  TABLE 17                                                         ______________________________________                                                                 Product Triphenyl-                                              Starting 1-Alkyn-                                                                             methoxy Substituted                                    Example  4-ol of Example                                                                               1-Alkyne                                               ______________________________________                                         143      116            4-triphenylmethoxy-5-                                                          trans-nonen-1-yne                                      144      120            5-methyl-4-triphenyl-                                                          methoxy-1-octyne                                       145      121            5-methyl-4-triphenyl-                                                          methoxy-1-nonyne                                       146      124            4-triphenylmethoxy-5-                                                          trans-octen-1-yne                                      147      141            (R)-4-triphenylmeth-                                                           oxy-1-octyne                                           148      142            (S)-4-triphenylmeth-                                                           oxy-1-octyne                                           148a     124a           4-triphenylmethoxy-5-                                                          trans-decen-1-yne                                      ______________________________________                                    

EXAMPLES 149-154

The product triphenylmethoxy substituted 1-iodo-1-trans-alkenes of Table 18 below are prepared from the starting triphenylmethoxy substituted 1-alkynes of the table by the procedure described in Example 107.

                  TABLE 18                                                         ______________________________________                                              Starting Tri-                                                                  phenylmethoxy                                                                  Substituted 1-Al-                                                                           Product Triphenylmethoxy Substituted                         Ex.  kyn of Example                                                                              1-Iodo-trans-1-alkene                                        ______________________________________                                         149  143          1-iodo-4-triphenylmethoxy-trans,trans-                                         1,5-nonadiene                                                150  144          1-iodo-5-methyl-4-triphenylmethoxy-                                            trans-1-octene                                               151  145          1-iodo-5-methyl-4-triphenylmethoxy-                                            trans-1-nonene                                               152  146          1-iodo-4-triphenylmethoxy-trans,trans-                                         1,5-octadiene                                                153  147          (R)-1-iodo-4-triphenylmethoxy-1-trans-                                         octene                                                       154  148          (S)-1-iodo-4-triphenylmethoxy-1-trans-                                         octene                                                       154a 148a         1-iodo-4-triphenylmethoxy-trans,trans-                                         1,5-decadiene                                                ______________________________________                                    

EXAMPLE 155 Preparation of ethyl-p-fluorophenoxy-acetate

To a stirred solution of 50 g (0.29 moles) of p-fluorophenoxy acetic acid in one liter of absolute ethanol is added 10 ml of sulfuric acid. The mixture is heated to reflux for 18 hours, cooled to room temperature, and evaporated under vacuum. It is then poured onto 300 g of ice, extracted twice with 500 ml of ether, washed twice with 250 ml of a saturated solution of sodium bicarbonate, 100 ml of saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated under vacuum giving 58 g of an oil. This is crystallized from 50 ml of hexane at -25° C. to give 55 g (90%) of the subject product as colorless crystals, mp 32°-33° C.

EXAMPLE 156 Preparation of p-fluorophenoxy acetaldehyde

To a stirred solution of 1.98 g (10 mmoles) of ethyl-p-fluorophenoxy acetate (Example 155) in 15 ml of dry toluene, cooled to -78° C., under argon, is added, dropwise over 30 minutes, 8 ml of a 1.4 M solution of diisobutylaluminum hydride in toluene (11 mmoles). The mixture is stirred for 2 hours at -78° C., 1 ml of methanol is added, followed by 5 ml of water, dropwise. The gel formed is filtered through Celite and washed with 100 ml of ether, portionwise. The organic phase is separated, washed twice with 25 ml of a saturated brine solution, dried with magnesium sulfate, filtered, and evaporated. The oil obtained is distilled at 71°-73° C. (0.1 mm) to give 600 mg (45%) of the subject product as a colorless liquid.

EXAMPLE 157 Preparation of 3-hydroxy-4-p-fluorophenoxy-1-butyne

Acetylene gas, dried by passing through a trap containing sulfuric acid, is bubbled at a moderate rate, through 5 ml of vigorously stirred tetrahydrofuran, for 15 minutes. To this acetylenic solution, is then added dropwise, with continued passage of acetylene, 3.5 ml of a 2.4 M solution of n-butylmagnesium chloride in tetrahydrofuran (8.4 mmoles) over 45 minutes. The mixture is stirred a further 15 minutes, and a solution of 580 mg (3.9 mmoles) of p-fluorophenoxy acetaldehyde (Example 156) in 3 ml of tetrahydrofuran is added dropwise over 15 minutes. This solution is stirred for 2 more hours, with passage of acetylene, poured into 50 ml of a saturated solution of ammonium chloride, extracted twice with 50 ml of ether, washed with 10 ml of ammonium chloride solution, dried with magnesium sulfate, filtered, and evaporated. The crude subject product is purified by sublimation at 75° C. (0.1 mm) for 5 hours to give 330 mg (48%) of white crystals, mp 46°-47° C.

EXAMPLE 158 Preparation of 4-p-fluorophenoxy-3-trimethylsilyloxy-1-butyne

To a 0° C. solution of 10 g (55 mmoles) of 3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of dry dimethylformamidee and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then poured into 150 ml of hexane and 100 ml of ice-water. Thhe organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.

EXAMPLE 159 Preparation of 1-tri-n-butylstannyl-4-p-fluorophenoxy-3-trimethylsilyloxy-trans-1-butene

A mixture of 2.52 g (10 mmoles) of 3-trimethylsilyloxy-4-p-fluorophenoxy-1-butyne (Example 158), 2.91 g (10 mmoles) of tri-n-butyl-tin hydride, and 10 mg of azobisisobutyronitrile is heated, under an argon atmosphere, with stirring, for 2 hours at 140° C. After cooling to room temperature, the crude reaction mixture is fractionally distilled at 180°-185° C. (0.05 mm), to give 4.6 g (85%) of the subject product as a colorless liquid.

EXAMPLES 160-162

The product esters of Table 19 below are obtained by the procedure described in Example 155.

                  TABLE 19                                                         ______________________________________                                                 Starting Aryloxy                                                                              Product Aryloxy                                         Example Acid           Ethyl Ester                                             ______________________________________                                         160     p-chlorophenoxy-                                                                              ethyl p-chlorophenoxy-                                          acetic acid    acetate                                                 161     3,4-dichlorophe-                                                                              ethyl-3,4-dichlorophe-                                          noxyacetic acid                                                                               noxyacetate                                             162     phenoxyacetic acid                                                                            ethyl phenoxyacetate                                    ______________________________________                                    

EXAMPLE 163 Preparation of ethyl-m-trifluoromethylphenoxy-acetate

A mixture of 100 g (0.618 mole) of α,α,α-trifluoro-m-cresol, 106 g (0.632 mole) of ethyl bromoacetate, 87.5 g (0.632 mole) of potassium carbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, and at room temperature for 18 hours. The mixture is filtered, evaporated under vacuum on a rotorary evaporator at 45° C. and at 85° C. (0.1 mm) to remove excess ethyl bromoacetate. The reaction mixture is taken up in 500 ml of ether, washed three times with 100 ml each of 0.1 M potassium carbonate, once with 100 ml of water, 100 ml of 0.01 M hydrochloric acid, and 100 ml of water. It is then dried with magnesium sulfate, filtered and evaporated, giving 142 g of the crude product. This is fractionally distilled at 73°-75° C. (0.1 mm) to give 124 g of the purified subject product as a colorless liquid.

EXAMPLES 164-166

The product esters of Table 20 are obtained by treating the starting phenols with ethyl bromoacetate by the procedure of Example 162.

                  TABLE 20                                                         ______________________________________                                         Example  Starting Phenol                                                                              Product Ester                                           ______________________________________                                         164      p-bromophenol ethyl p-bromophenoxy-                                                          acetate                                                 165      4-t-butylphenol                                                                              ethyl 4-t-butylphenoxy-                                                        acetate                                                 166      p-methoxyphenol                                                                              ethyl p-methoxyphenoxy-                                                        acetic acid                                             ______________________________________                                    

EXAMPLES 167-173

Following the procedure of Example 156, the starting esters of Table 21 are treated with diisobutylaluminum hydride to provide the product aldehydes of the table.

                  TABLE 21                                                         ______________________________________                                         Example Starting Ester                                                                              Product Aldehyde                                          ______________________________________                                         167     163          m-trifluoromethylphenoxy                                                       acetaldehyde                                              168     164          p-bromophenoxy acetalde-                                                       hyde                                                      169     165          4-t-butylphenoxy acetal-                                                       dehyde                                                    170     166          p-methoxyphenoxy acetalde-                                                     hyde                                                      171     160          p-chlorophenoxy acetalde-                                                      hyde                                                      172     161          3,4-dichlorophenoxy acet-                                                      aldehyde                                                  173     162          phenoxyacetaldehyde                                       ______________________________________                                    

EXAMPLES 174-180

Following the procedure of Example 156, treatment of the starting aldehyde of Table 22 with acetylene magnesium chloride provides the product alkynes of Table 22.

                  TABLE 22                                                         ______________________________________                                                  Starting                                                              Example  Aldehyde   Product Aryloxy Alkyne                                     ______________________________________                                         174      167        3-hydroxy-4-m-trifluoromethyl-                                                 phenoxy-1-butyne                                           175      168        3-hydroxy-4-p-bromophenoxy-1-                                                  butyne                                                     176      169        3-hydroxy-4-t-butylphenoxy-1-                                                  butyne                                                     177      170        3-hydroxy-4-p-methoxyphenoxy-                                                  1-butyne                                                   178      171        3-hydroxy-4-p-chlorophenoxy-                                                   1-butyne                                                   179      172        3-hydroxy-4-(3,4-dichlorophe-                                                  noxy)-1-butyne                                             180      173        3-hydroxy-4-phenoxy-1-butyne                               180a     a          3-hydroxy-5-phenyl-1-pentyne                               180b     b          3-hydroxy-5-(p-chlorophenyl)-                                                  1-pentyne                                                  180c     c          3-hydroxy-5-(p-methoxyphenyl)-                                                 1-pentyne                                                  180d     d          3-hydroxy-5-(m-trifluorometh-                                                  ylphenyl)-1-pentyne                                        ______________________________________                                          a hydrocinnamaldehyde.sup.1                                                    b pchlorohydrocinnamaldehyde.sup.1                                             c pmethoxyhydrocinnamaldehyde.sup.1                                            d mtrifluoromethylhydrocinnamaldehyde.sup.2                                    .sup.1 Billman, et al., Synthetic Communications, 1, 127-131 (1971).           .sup.2 Lednicer, Journ. Med. Chem., 11, 1258 (1968).                     

EXAMPLES 181-186

Treatment of the starting alkynes of Table 23 by the procedure of Example 158 followed by treatment of the procedure of Example 159 provides the product (E) 1-tri-n-butyltin-1-alkenes of the table.

                  TABLE 23                                                         ______________________________________                                              Starting                                                                  Ex.  Alkyne   Product (E)-1-tri-n-butyltin-1-alkene                            ______________________________________                                         130  174      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                m-trifluoromethylphenoxy-1-butene                                181  175      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                p-bromophenoxy-1-butene                                          182  176      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                t-butylphenoxy-1-butene                                          183  177      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                p-methoxyphenoxy-1-butene                                        184  178      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                p-chlorophenoxy-1-butene                                         185  179      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-                                  3,4-dichlorophenoxy-1-butene                                     186  180      (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-4-                                phenoxy-1-butene                                                 186a  48      (E)-1-tri-n-butylstannyl-4,4-trimethylene-3-                                   trimethylsilyloxy-(Z)-6-octadiene                                186b 180a     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                                phenyl-1-pentane                                                 186c 180b     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                                (p-chlorophenyl)-1-pentene                                       186d 180c     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                                (p-methoxyphenyl)-1-pentene                                      186e 180d     (E)-1-tri-n-butylstannyl-3-trimethylsilyloxy-5-                                (m-trifluoromethylphenyl)-1-pentene                              ______________________________________                                    

EXAMPLE 187 Preparation of 1-chloro-1-octen-3-one

This compound is prepared according to the procedure of Price and Pappalardo [C. C. Price and J. A. Pappalardo, Org. Syn., 32, 27 (1952)] from hexanoyl chloride, acetylene, and aluminum chloride in 94% yield, bp 51°-52° C. (0.1 mm); λ max 1680, 1595, 941 cm⁻¹.

EXAMPLE 188 Preparation of 1-iodo-1-octen-3-one

A mixture of 25 g (0.16 moles) of 1-chloro-1-octen-3-one (Example 187) and 35 g (0.23 moles) of sodium iodide in 200 ml of reagent acetone is stirred at the reflux temperature for 18 hours. The cooled mixture is filtered and the mother liquor taken to dryness. The residual oil is dissolved in benzene and the solution is washed with 5% sodium thiosulfate solution, saturated sodium chloride solution, dried and taken to dryness. The residual oil is crystallized from hexane to give 26 g of a white solid, mp 35°-37° C.; λ max 1670, 950 cm⁻¹.

EXAMPLE 189 Preparation of 3-hydroxy-1-iodo-3-methyl-1-octene

To a Grignard solution prepared from 1.05 g (0.41 moles) of magnesium and 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether under argon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45 ml of ether. The resulting solution is stirred at ambient temperature for one hour. After the addition of 75 ml of saturated ammonium chloride the ether layer is separated and the aqueous layer is separated and the aqueous layer is extracted several times with ether. The coombined ether extracts are washed successively with ammonium chloride and water, dried and taken to dryness to give 9.24 g of product as an oil; λ max 2.89, 3.23, 6.24 and 10.5.

EXAMPLE 190 Preparation of 1-iodo-3-methyl-3-trimethylsilyloxy-1-octene

To a stirred solution of 11.7 g of 3-hydroxy-1-iodo-3-methyl-1-octene (Example 184) and 7.4 g of imidazole in 45 ml of dry dimethylformamide is added dropwise 5.98 g of trimethylsilylchloride at 0° C. under argon atmosphere. After stirring at 0° C. for an additional 15 minutes, the solution is stirred at ambient temperature for 18 hours. The reaction mixture is poured into 600 ml of hexane and the resulting solution washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and taken to dryness to furnish 14.7 g of oil. Distillation affords 13.4 g of clear oil; bp 65° C. (0.05 mm); λ max 6.21, 8.00, 9.90, 10.51, 11.90, 13.2μ.

EXAMPLE 190a Preparation of 1-iodo-3-methyl-3-trimethylsilyloxy-1-decene

Treatment of octanoylchloride by the procedures of Example 187 followed by treatment of the resulting 1-chloro-1-decen-3-one by the procedure of Example 188 followed by treatment according to Examples 189 and 190 is productive of the named compound.

EXAMPLE 191 Preparation of 4-trimethylsiloxy-1-octyne

To a cold solution of 166 g of 4-hydroxy-1-octyne [Prostaglandins, 10, 289 (1975)], and 240 g of imidazole in one liter of dimethylformamide is added dropwise 202 g of chlorotrimethylsilane. The mixture is allowed to stand at room temperature for 2 to 3 days. The mixture is partitioned with water and hexane. The hexane layer is washed with brine, dried over magnesium sulfate, and concentrated. Distillation of the residue gives a colorless liquid, bp 38° C. (0.2 mm).

EXAMPLE 192 Preparation of 1-iodo-4-trimethylsiloxy-trans-1-octene

To a stirred solution of 0.20 moles of freshely prepared bis-(3-methyl-2-butyl)borane in 300 ml of tetrahydrofuran at 0°-5° C. is added dropwise a solution of 19.8 g of 4-trimethylsiloxy-1-octyne in 30 ml of tetrahydrofuran. The resulting mixture is stirred at ambient temperature for several hours, cooled in an ice bath, and treated with 53 g of trimethylamine oxide. The mixture is stirred several hours at 25°-40° C. and then poured into 2 liters of 15% sodium hydroxide. The resulting mixture is treated immediately with a solution of 140 g of iodine in 300 ml of tetrahydrofuran. After 0.5 hour the organic phase is-separated and the aqueous phase is extracted with ether. The combined organic layers are washed with water, sodium thiosulfate solution, and brine; dried over magnesium sulfate; and concentrated to give an oil, pmr spectrum (CDCl₃): 6.2 (d, ICH═) and 6.7 (quintuplet, ═CH--).

EXAMPLE 193 Preparation of 4-hydroxy-1-iodo-trans-1-octene

A 23 g portion of 1-iodo-4-trimethylsilyloxy-1-octene is dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and 50 ml of water. Concentration provides the named product.

EXAMPLE 194 Preparation of 4-trimethylsiloxy-4-vinyl-1-iodo-trans-1-octene

To a stirred solution of 456 mg of 4-hydroxy-4-vinyl-1-iodo-trans-1-octene and 320 mg of imidazole in 1.0 ml of dimethylformamide is added 0.23 ml of chlorotrimethylsilane during 3 minutes. The mixture is stirred at room temperature for 22 hours and partitioned with a mixture of cold hexane and water. The hexane layer is washed repeatedly with water and then brine, dried over magnesium sulfate, and concentrated to give an oil, pmr spectrum (CDCl₃): 0.13 (s, trimethylsiloxy group) and 2.32 (d, ═CHCH₂).

EXAMPLE 195 Preparation of n-butyl cyclopropyl ketone

To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (748 mmoles) in about 750 ml of 2:1 ether-hexane during one hour at 5°-10° C. The resulting suspension is diluted with 300 ml of ether and stirred at room temperature for 2 hours and at reflux for 2 hours. The mixture is cooled and poured into several portions of 1:1 ice:4 N hydrochloric acid. The ethereal phases are combined and washed with brine, sodium carbonate solution, and brine. The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, bp-102°-104° C. (80 mm), pmr spectrum (CDCl₃): δ 2.55 (triplet, --CH₂ CO--).

EXAMPLE 196 Preparation of 4-cyclopropyl-4-hydroxy-1-octyne

To a stirred, refluxing suspension of amalgum prepared from 6.2 g of magnesium and 50 mg of mercuric chloride suspended in 60 ml of ether is added a solution of a mixture of 30.4 g of n-butyl cyclopropyl ketone (Example 189) and 29.8 g of propargyl bromide in 65 ml of ether during 60 minutes. After reaction at reflux temperature for an additional 30 minutes, the mixture is cooled to 0° C. and treated with 35 ml of saturated ammonium chloride. The mixture is diluted with ether and filtered through Celite. The filtrate is washed with brine, dried over potassium carbonate, and concentrated. The resiidue is distilled to provide a liquid, δ 0.43 (cyclopropyl hydrogens), 2.07 (triplet, HC.tbd.C), and 2.44 (doublet, C.tbd.CCH₂).

EXAMPLE 197 Preparation of 4-cyclopropyl-4-trimethylsiloxy-1-octyne

To a stirred solution of 27.8 g of 4-cyclopropyl-4-hydroxy-1-octyne (Example 190) and 33.3 g of imidazole in 130 ml of dimethylformamide at 5° C. is added 24 ml of chlorotrimethylsilane during 5 minutes. The solution is stirred at ambient temperature for 17 hours and then partitioned with 600 ml of hexane and 250 ml of ice water. The hexane phase is separated and washed successively with water and brine. The solution is dried over magnesium sulfate and evaporated to give a liquid, pmr spectrum (CDCl₃): δ 0.12 (singlet, trimethylsiloxy group), 2.02 (triplet, HC.tbd.C), and 2.45 (doublet, C.tbd.CH₂).

EXAMPLE 198 Preparation of 4-cyclopropyl-4-trimethylsiloxy-1-(tri-n-butylstannyl)-trans-1-octene

A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-1-octyne (Example 191), 28 ml of tri-n-butyltin hydride, and 50 mg of azobisisobutyronitrile under nitrogen is ehated to 85° C. After the resulting exothermic reaction subsides the mixture is heated at 130° C. for one hour. The crude product is evaporatively distilled to give a liquid, pmr spectrum (CDCl₃): δ 0.10 (trimethylsiloxy group), 2.33 (doublet, ═CHCH₂), and 6.02 (vinyl hydrogens).

EXMAPLES 199-204

Treatment of the starting carboxylic acids of Table 24 with the appropriate alkyllithium by the method of Example 190 provides the product ketones of the table.

                                      TABLE 24                                     __________________________________________________________________________           Starting                                                                 Example                                                                              Carboxylic Acid                                                                          Alkyl Lithium                                                                           Product Ketone                                        __________________________________________________________________________     199   cyclopropane                                                                             n-hexyllithium                                                                          n-hexylcyclopropyl ketone                                   carboxylic acid                                                          200   cyclopropane                                                                             n-propyllithium                                                                         n-propylcyclopropyl ketone                                  carboxylic acid                                                          201   acrylic acid                                                                             n-hexyllithium                                                                          n-hexylvinyl ketone                                   202   acrylic acid                                                                             n-propyllithium                                                                         n-propylvinyl ketone                                  203   crotonic acid                                                                            n-butyllithium                                                                          n-butyl-1-propenyl ketone                             204   crotonic acid                                                                            n-hexyllithium                                                                          n-hexyl-1-propenyl ketone                             __________________________________________________________________________

EXAMPLES 205-210

Treatment of the starting ketones of Table 25 with propargymagnesium bromide by the procedure of Example 190 followed by treatment with chlorotrimethylsilane by the procedure of Example 191 followed by treatment with tri-n-butyltin hydride by the method of Example 192 is productive of the vinylstannyl derivatives of the table.

                  TABLE 25                                                         ______________________________________                                                Starting                                                                Example                                                                               Ketone    Product Vinylstannyl Derivative                               ______________________________________                                         205    193       (E)4-trimethylsilyloxy-4-cyclopropyl-1-                                        tri-n-butylstannyldecene                                      206    194       (E)4-trimethylsilyloxy-4-cyclopropyl-1-                                        tri-n-butylstannylheptene                                     207    195       (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                                        butylstannyldecene                                            208    196       (E)4-trimethylsilyloxy-4-vinyl-1-tri-n-                                        butylstannylheptene                                           209    197       (E)4-trimethylsilyloxy-4-(1-propenyl)-1-                                       tri-n-butylstannyloctene                                      210    198       (E)4-trimethylsilyloxy-4-(1-propenyl)-1-                                       tri-n-butylstannyldecene                                      ______________________________________                                    

EXAMPLE 211 Preparation of 1-propargyl-1-hydroxycyclohexane

A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-l. of anhydrous ether is treated with 0.6 g of mercuric chloride and about 100 mg of iodine. After several minutes, 3 ml of propargyl bromide is added and if no exotherm is noted, a small amount of reacting propargyl bromide and magnesium in ether is added. When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at a rate that produces vigorous refluxing of the solution. (The propargyl bromide must always be present in some excess otherwise the reaction will stop. If this happens, the addition of about 1 ml of propargyl bromide will restart the reaction.) After about half of the propargyl bromide-cyclohexanone mixture has been added, another 500-750 ml of ether is used to dilute the reaction mixture. At the end of the addition, the reaction mixture is refluxed for at least 0.5 hour, cooled and poured into 4 liters of saturated ammonium chloride during good stirring. The ethereal layer is separated and the aqueous layer is washed with ether several times and the combined extract is washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane.

EXAMPLE 212 Preparation of 1-Ethynyl-1-trimethylsilyloxycyclohexane

A 194 g portion of imidazole and 158.2 g of 1-ethynylcyclohexan-1-ol are mixed with 500 g of dimethylformamide with cooling in an ice bath. A 152 g portion of trimethylchlorosilane is added with cooling and stirring in about one minute. The mixture is stirred for one hour and allowed to stand overnight. One liter of hexane is added. The lower layer is separated, diluted with water and extracted with hexane. The hexane layers are washed several times with water and then combined and dried over magnesium sulfate. Filtration and then evaporation of the hexane gives 198.5 g of product which is distilled giving 168 g of the desired product.

EXAMPLE 213 Preparation of 1-Propargyl-1-trimethylsilyloxycyclohexane

To a stirred solution of 55.4 g of 1-(2-propyn-1-yl)cyclohexanol [H. Gutmann, et. al., Helv. Chim. Acta, 42, 719 (1959)] and 79 g of imidazole in 240 ml of DMF at 10° C. initially is added 56 ml of chlorodimethylsilane during 10 minutes. The cloudy yellow solution is stirred at room temperature for 26 hours. The resulting mixture is partitioned between 1000 ml of hexane and 400 ml of water at 0°-5° C. The hexane phase is washed successively with 6×200 ml of cold water and 200 ml of brine. The extract is dried over magnesium sulfate, filtered, and evaporated to give 85 g of colorless liquid, i.r. (film): 1240 and 830 cm⁻¹ (trimethylsilyloxy group).

EXAMPLE 214 Preparation of 1R,2S(and 1S,2R)-1-Ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and 1S,2S)- 1-ethynyl-1-hydroxy-2-butylcyclopentane

Into 150 ml of dry tetrahydrofuran is bubbled purified acetylene, as a solution of 2.4 M n-butyl magnesium chloride (92 ml) is added dropwise with stirring over a 2 hour period. To the resulting solution of acetylene magnesium chloride is added 21 g of 2-butylcyclopentanone in 50 ml of tetrahydrofuran dropwise over 15 minutes. The solution is stirred for 30 minutes and then is poured into an ice cold solution of saturated ammonium chloride. The mixture is acidified to pH 5 and extracted with ether. The ether solution is washed with brine and dried over magnesium chloride. The ether is removed and the residue is distilled giving 14.8 g of a colorless liquid. This is chromatographed on a dry column of silica-gel eluting with benzene-ethyl acetate (19:1) to separate isomers giving 1R,2S(and 1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 1R,2R(and 1S,2S)-1-ethynyl-1-hydroxy-2-butylcyclopentane.

EXAMPLE 215 Preparation of 1R,2S(and 1S,2R)-1-Ethynyl-1-trimethylsilyloxy-2-butylcyclopentane

To a solution of 29.4 g of 1R,2S(and 1S,2R)-1-ethynyl-1-hydroxy-2-butylcyclopentane and 30.2 g of imidazole in 180 ml of dimethylformamide is added at 0° C. with stirring 24.1 g of trimethylsilylchloride. The mixture is stirred for 3 hours. The mixture is poured into 700 ml of hexane and washed twice with water and once with brine. The ether solution is dried over magnesium sulfate. The solvent is removed and the residue is distilled (bp 64°-72° C., 0.6 mm) to give 35.8 g of 1R,2S(and 1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane.

EXAMPLE 216 Preparation of 1R,2S(and 1S,2R)-1-trans-2-Iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 9.2 g of sodium borohydride and 45.8 g of 2-methyl-2-butene in 350 ml of dry tetrahydrofuran at 0° C. with stirring under nitrogen is added, over 20 minutes, 41.1 ml of boron trifluoride etherate. After 3 hours, to this resulting solution of diisoamylborane is added 38.8 g of 1R,2S(and 1S,2R)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 40 ml of tetrahydrofuran in 20 minutes. The mixture is ttirred 2 hours and then stored at -20° C. overnight. The mixture is allowed to warm to 0° C. and at 0° C. 85 g of dry trimethylamineoxide is added portionwise over 20 minutes. After stirring at 25° C. for one hour, the mixture is filtered through diatomaceous earth. The filtrate is poured simultaneously with a solution of 230 g of iodine in 250 ml of tetrahydrofuran into a stirred, cold solution of 430 g of sodium hydroxide in 1900 ml of water. After stirring for 30 minutes, the organic layer is separated. The aqueous layer is extracted with ether. The combined organic solutions are washed twice with a saturated solution of sodium thiosulfate and once with brine. The solution is dried over magnesium sulfate, the solvent is removed and the residue is dissolved in hexane. The hexane solution is filtered through diatomaceous earth and silica gel. The hexane is removed and the residue is purified by dry column chromatography on silica gel eluting with hexane: 45.35 g of 1R,2S(and 1S,2R)-1-(trans-2-iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane is obtained.

EXAMPLES 217-218

In the manner of Example 216 described above, the following acetylenic alcohols listed in Table 26 were prepared from the acetylenic Grignard reagent and the ketone specified.

                                      TABLE 26                                     __________________________________________________________________________     Example                                                                             Grignard Reagent                                                                          Ketone  Acetylenic Alcohol                                     __________________________________________________________________________     217  acetylene magnesium                                                                       cyclohexanone                                                                          1-ethynyl-1-hydroxycyclohexane                              chloride                                                                       Method A                                                                  218  acetylene magnesium                                                                       cyclopentanone                                                                         1-ethynyl-1-hydroxycyclopentane                             chloride                                                                       Method A                                                                  __________________________________________________________________________

EXAMPLE 219 Preparation of 1-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane

To a stirred mixture of 31.5 g of 1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. The stirred mixture is heated to about 80° C. The initial exothermic reaction is moderated, and the temperature is subsequently maintained at 130°-135° C. for one hour.

The product is distilled to afford 56 g of colorless liquid, bp 150°-160° C. (0.15-0.3 mm), pmr (CDCl₃): 6.0 (multiplet, vinyl protons).

EXAMPLES 220-221

Using the procedure outlined above for Example 213, the acetylenic alcohols listed in Table 27 are converted to their corresponding acetylenic trimethylsilyloxy derivatives; these in turn using the procedure outlined above for Example 216, were converted to their corresponding trans-2-iodovinyl derivatives.

                  TABLE 27                                                         ______________________________________                                              Acetylene                                                                 Ex.  of Example                                                                               Vinyl Iodide Compound                                           ______________________________________                                         220  217       1-(trans-2-iodovinyl)-1-trimethylsilyloxy-                                     cyclohexane                                                     221  218       1-trans-2-iodovinyl)-1-trimethylsilyloxy-                                      cyclopentane                                                    ______________________________________                                    

EXAMPLE 222 Preparation of 1-(3-Tri-n-butylstannyl)-2-trans-propenyl)-1-trimethylsilyloxycyclopentane

Treatment of cyclopentanone by the sequential reactions described by Examples 211, 213 and 219 is productive of the title compound.

EXAMPLE 223 Methyl Nat. 15α-hydroxy-9-oxo-11α/β(2-hydroxyethylthio)-5-cis,13-trans-prostadienoate

A solution of 2 g of nat. PGA₂ methyl ester (U.S. Pat. No. 3,759,965) and 448 mg of 2-mercaptoethanol is stirred under argon. One drop of triethylamine is added and the reaction mixture is stirred for 4 hours and 15 minutes. A 180 mg portion of the reaction mixture is chromatographed on a one mm silica gel preparative plate, eluting with ethyl acetate:benzene (2:3). A 2,4-dinitrophenylhydrazone positive band 1/4 to 11/2 inches above the origin is removed and the product is eluted with 20% methanol in chloroform. This eluate is evaporated giving 97 mg of the product (A) as a pale yellow oil.

The remainder of the reaction mixture is chromatographed similarly on four silica gel preparative plates 2 mm thick. The product (B) is isolated as above and combined with (A) giving 1.55 g of the desired product as a yellow oil.

EXAMPLE 224 11α/β-(2-hydroxy ethylthio)-15-hydroxy-15-methyl-9-oxo-5-cis,13-trans-prostadienoic acid

A mixture of 200 mg of all racemic 15 methyl PGA₂ (U.S. Pat. No. 3,919,286), 57 mg of mercaptoethanol and 60 mg of triethylamine is stirred under argon. One additional drop of triethylamine is added and the mixture is stirred for 2 hours. The mixture is acidified with 5% HCl, extracted with ether, the ether is washed with a saturated solution of sodium chloride and then dried over sodium sulfate. The residue is chromatographed on two 1 mm thick silica gel plates, eluting twice with ethyl acetate:benzene (1:4) containing 1.5% acetic acid. The yellow 2,4-dinitrophenylhydrazone positive band between 1/4 and 11/4 inches above the origin is removed from the silica with 20% methanol in chloroform, giving 143 mg of the desired product as an amber oil.

Example 225 11α/β-(2-hydroxy ethylthio)-16-hydroxy-16-methyl-9-oxo-5-cis,13-trans-prostadienoic acid

A solution of 4.2 g of E-1-iodo-4-methyl-4-trimethylsilyloxy-1-octene in 100 ml of dry ether is cooled in a dry ice-acetone bath under nitrogen and treated with 30.85 ml of t-butyl lithium via a syringe, over a period of 15 minutes. In a second flask a mixture of 1.61 g of copper pentyne and 5.4 ml of hexamethylphosphoramide in 70 ml of ether is stirred for 15 minutes until it becomes clear. This copper pentyne solution is added to the vinyl lithium solution via a syringe, over a period of 20 minutes. The mixture is stirred in the same bath for 1.5 hours and then a solution of 4.7 g of bis-THP-cyclopentenone in 70 ml of ether is added at -78° C. After stirring at -78° C. for 40 minutes, the cooling bath is replaced by an ice-acetone bath. Stirring is continued at -20° C. to -10° C. for 40 minutes. The reaction is quenched by the addition of 50 ml of cold, saturated aqueous ammonium chloride solution and the entire mixture is poured into 450 ml of cold, saturated aqueous ammonium chloride solution. The mixture is allowed to stand overnight in a refrigerator. The aqueous phase is separated and extracted twice with ether. The ether extracts are combined with the organic phase and washed with dilute aqueous HCl, water and finally brine. After evaporation of the solvents, the residue is dissolved in a mixture of 80 ml of acetic acid, 60 ml of tetrahydrofuran and 20 ml of water and stirred at room temperature for one hour. The mixture is poured into water and extracted with ether. The ether extract is washed with brine and the solvents are evaporated on a rotary evaporator in the presence of toluene. The residue is passed through a 250 g silica gel column packed in 10% ethyl acetate in hexane. Continuous elution with increasing percentage of ethyl acetate in hexane gives 2.33 g of product.

A 2.3 g portion of this product is dissolved in a mixture of 100 ml of acetic acid, 50 ml of tetrahydrofuran and 25 ml of water. The mixture is stirred and heated at 45°-50° C. for 3.5 hours. The mixture is worked up by repeating the above ether extraction and water and brine washing. The solvent is evaporated in the presence of toluene as above. The residue is passed through a 50 g silica gel column packed in 30% ethyl acetate in hexane. Continuous elution with increasing percentage of ethyl acetate in hexane gives 1.09 g of product.

A solution of 157 mg of the above compound in 85 ml of tetrahydrofuran and 5 ml of 1.5N HCl is stirred under a nitrogen atmosphere at room temperature for 48 hours. The reaction mixture is diluted with brine and extracted with 80 ml of ether in two portions. The combined ether extracts are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil. This oil is chromatographed using a 2000μ preparative thin layer plate, eluting with ethyl acetate:benzene (2:3) containing 2% acetic acid. The product is located and then eluted from the silica gel with 20% methanol in chloroform giving 122 mg of yellow oil.

To a stirred solution of the 122 mg of the previous compound, 56 mg of β-mercaptoethanol and one ml of tetrahydrofuran, at room temperature, is added 14 drops of triethylamine. The reaction mixture is stirred for 3 hours and then chromatographed using one 1 mm preparative thin layer silica gel plate, eluting with ethyl acetate:benzene (2:3) containing 2% acetic acid. The product is located and eluted from the silica gel with 20% methanol in chloroform giving 52 mg of the desired product as a yellow oil.

Example 226 11α/β(2-hydroxyethylthio)-16-hydroxy-9-oxo-13-trans-prostenoic acid

To a stirred solution of 8.57 g of (E)-1-tributylstannyl-4-triethylsilyloxy-1-octene and 10 ml of anhydrous tetrahydrofuran, cooled to -70° C. under an argon atmosphere, is slowly added 7.0 ml of n-butyl lithium. After 15 minutes the reaction mixture is warmed to -40° C. for 2 hours. The reaction mixture is recooled to -78° C. A solution of 2.2 g of copper pentyne and 6.85 g of tri-n-butyl phosphine in 27 ml of ether is added. After 2 hours a 4.60 g portion of cyclopentenone and 15 ml of anhydrous ether is added. After 30 minutes, the reaction mixture is warmed to -35° C. to -40° C. for one hour and then at 30° C. to 35° C. for 30 minutes. The reaction mixture is cooled to -40° C. and to it is slowly added 5 ml of acetic acid. The reaction mixture is poured into a mixture of 400 ml of saturated aqueous ammonium chloride and 250 ml of ether and is vigorously stirred for one hour. The aqueous phase is separated and extracted with 400 ml of ether in three portions. The ether phases are combined, washed with 1% H₂ SO₄, dried over magnesium sulfate, filtered and concentrated in vacuo giving 22.7 g of amber liquid.

A solution of 22.7 g of the above liquid in 250 ml of a mixture of acetia acid-tetrahydrofuran:water (4:2:1) is stirred under an argon atmosphere at room temperature for one hour. The reaction mixture is diluted with toluene and concentrated in vacuo giving 19.7 g of brown liquid.

This 19.7 g of liquid is dry column chromatographed using 1500 g of silica gel and eluted with ethyl acetate:benzene (2:3) containing 2% acetic acid. A total of 900 ml is collected. The column is cut into one inch segments, Like fractions are combined after thin layer chromatographic analysis. The product is eluted from the silica with 20% methanol in chloroform giving 1.6 g. An additional 326 mg was obtained upon further chromatographing impure fractions.

A solution of 325 mg of the oil in 13 ml of tetrahydrofuran and 10 ml of 1.5N HCl is stirred under nitrogen, at room temperature for 48 hours. The reaction mixture is diluted with brine and extracted with 125 ml of ether in two portions. The combined ether extracts are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo giving a yellow oil.

This yellow oil is chromatographed using two 2000μ preparative thin layer plates and diluting with ethyl acetate:benzene (2:3) containing 2% acetic acid. The product is located and eluted from the silica gel with 20% methanol in chloroform giving 189 mg of a yellow oil.

To a stirred solution of the 189 mg of oil, 60 mg of β-mercaptoethanol and one ml of tetrahydrofuran at room temperature is added 17 drops of triethylamine. The reaction mixture is stirred for 3 hours and then chromatographed using one 1 mm preparative thin layer silica gel plate and eluting with ethyl acetate:benzene (2:3) containing 2% acetic acid. The product is located and eluted from the silica gel with 20% methanol in chloroform giving 111 mg of the desired final product as a yellow oil.

Example 227 Erythro-11α/β-(2-hydroxyethylthio)-15α,16-dihydroxy-9-oxo-5-cis,13-trans-prostadienoic acid

A 3.10 g portion of erythro(E)-1-iodo-3,4-isopropylidenedioxy-1-octene is reacted with 29 ml of 0.8N-t-butyl-lithium in hexane with 60 ml of ether for 2 hours. A solution in ether at -78° C. of 10 mmol of lithium thiophenoxide with 3.95 g (10.0 mmol) of tri-n-butylphosphine copper iodide is next added for one hour, then is added 3.44 g of bis-THP cyclopentenone at -20° C. for 11/2 hours. The reaction mixture is quenched and worked up with ammonium chloride. This crude product is partially deblocked with 125 ml of acetic acid:tetrahydofuran:water (5:5:2) at room temperature for 2 hours. After removal of the solvents by azeotroping 3 times with toluene at 50° C., the crude product is chromatographed on a dry-column of silica gel with 2:3 ethylacetate in benzene with 2% of acetic acid. The column is cut into 11/2 inch segments and like fractions are combined giving 2.10 g of product.

A solution of 400 mg of the above PG acetonide in 15 ml of acetic acid:tetrahydrofuran:water (4:2:1) is stirred at 50° C. under an argon atmosphere for 3 hours. The reaction mixture is cooled, diluted with toluene and concentrated in vacuo giving a yellow oil.

This oil is stirred in a mixture of 15 ml of tetrahydrofuran and 12 ml of 1.5N HCl under an argon atmosphere at room temperature for 48 hours. The reaction mixture is diluted with brine and extracted with 120 ml of ether in two portions. The combined ether extracts are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo giving a yellow oil. This oil is chromatographed using two 2000μ preparative thin layer silica gel plates, eluting with ethyl acetate:benzene (2:3) containing 2% acetic acid. The product is located and eluted from the silica gel with 20% methanol in chloroform giving 88 mg.

To a stirred solution of the above 88 mg of product, one ml of tetrahydrofuran and 126 mg of β-mercaptoethanol at room temperature, is added 8 drops of triethylamine The reaction mixture is stirred for 3 hours and then chromatographed using one 2 mm preparative thin layer plate and eluting twice with ethyl acetate:benzene (2:3) containing 2% acetic acid. The product is located and eluted from the silica gel with 20% methanol in chloroform. The eluent is concentrated in vacuo giving the desired product as a yellow oil.

Example 228 Nat. 11α/β-(2-hydroxyethylthio)-15α-hydroxy-9-oxo-13-transprostenoic acid

To a mixture of 100 mg of nat. PGA₁ (U.S. Pat. No. 3,725,469) and 33 mg of triethylamine is added 24 mg of 2-mercaptoethanol. The reaction mixture is stirred under an argon atmosphere for 18 hours. Ether is added. An equal volume of 5% HCl is added giving complete two-phase solution. The ether is separated, washed three times with saturated sodium chloride solution, dried over sodium sulfate and taken to dryness giving a pale yellow oil comprising 123 mg of the desired product.

Column chromatography as described in Example 229 will provide the separated 11α and 11β epimers.

Example 229 Methyl Nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9-oxo-5-cis,13-trans-prostadienoate and methyl nat.-11β(2-hydroxyethylthio)-15α-hydroxy-9-oxo-5-cis,13-trans prostadienoate

A solution of 10 g (28.7 mmol) of nat.-PGA₂ methyl ester, 2.24 g (28.7 mmol) of 2-mercaptoethanol and 5 drops of triethylamine is stirred at ambient temperature under an argon atmosphere for 18 hours. The resulting oil is chromatographed on a 61 inch by 3 inch (flat) nylon tube packed with 1700 g of silica-gel. The column is developed with ethylacetate-benzene-acetic acid (20:30:1), and 2000 ml of eluant is collected. The column is then divided into 1-inch segments. Segments 12-17 are combined to furnish 2.64 g of nat.-11α-(2-hydroxyethylthio)-PGE₂ methyl ester; R_(f) 0.33 (ethylacetate-benzene-acetic acid/20:30:1, 3 elutions). Segments 18-23 are combined to give 2.83 g of a mixture of nat.-11α- and 11β-(2-hydroxyethylthio)-PGE₂ methyl ester; R_(f) 0.33, 0.26 (ethyl acetate-benzene-acetic acid/20:30:1, 3 elutions). Segments 24-36 are combined to give 2.46 g of nat.-11β-(2-hydroxyethylthio)-PGE₂ methyl ester; R_(f) 0.26 (ethylacetate-benzene-acetic acid/20:30:1, 3 elutions).

Examples 230-262

Addition of 2-mercaptoethanol to the A-prostaglandins of Table 28 by the method of Example 229 followed by silica-gel chromatography is productive of the separated 11α and 11β(2-hydroxyethylthio) prostanoic analogs.

                                      TABLE 28                                     __________________________________________________________________________     Example                                                                        __________________________________________________________________________     230  nat.-prostaglandin A.sub.1                                                                   nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-13-                                                                       trans-prostenoic acid and the corresponding                                    11β-isomer                                             231  prostaglandin A.sub.1                                                                        11α-(2-hydroxyethylthio)-15α-hydroxy-9-oxo-                        13-trans-                                                                      prostenoic acid and the corresponding                                          11β-(2-hydroxyethylthio)-15α-232 nat.-prosta                        glandin A.sub.2 nat.-11α-(l-hydroxyethylthio)-15.                        alpha. -hydroxy-9-oxo-5-cis,                                                   13-trans-prostadienoic acid and the corresponding                              11β-                                                                      isomer                                                      233  prostaglandin A.sub.2                                                                        11α-(2-hydroxyethylthio)-15α-hydroxy-9-oxo-                        5-cis,13-                                                                      trans-prostadienoic acid and the corresponding                                 11β-                                                                      isomer                                                      234  15-deoxy-16-hydroxy                                                                          Ethyl 11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-1                        3-trans-                                                         prostaglandin A.sub.1                                                                        prostenoate and the corresponding 11β-isomer                ethyl ester (U.S.                                                              Pat. No. 3,950,406)                                                       235  15-deoxy-16-hydroxy                                                                          Methyl 11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-                        13-                                                              prostaglandin A.sub.1                                                                        trans-prostenoate and the corresponding                                        11β-isomer                                                  methyl ester (U.S.                                                             Pat. No. 3,950,406)                                                       236  15-deoxy-16-hydroxy-17-                                                                      11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-17-meth                        yl-                                                              methyl-19,20-dinor                                                                           19,20-dinor-13-trans-prostenoic acid and the                     prostaglandin A.sub.1                                                                        corresponding 11β-isomer                                    (U.S. Pat. No. 3,950,406)                                                 237  15-deoxy-16-hydroxy-17-                                                                      11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-17-ethy                        l-20-                                                            ethyl-20-nor  nor-13-trans-prostenoic acid and the corresponding               prostaglandin A.sub.1                                                                        11β-isomer                                                  (U.S. Pat. No. 3,950,406)                                                 238  nat.-15-deoxy-16(R)-                                                                         nat.-11α-(2-hydroxyethylthio)-16(R)hydroxy-9-oxo-                        13-                                                              hydroxy prostaglandin A.sub.1                                                                trans-prostenoic acid methyl ester and the                                     corresponding                                                    methyl ester  11β-isomer                                                  (U.S. Pat. No. 3,950,406)                                                 239  nat.-15-deoxy-16(S)-                                                                         nat.-11α-(2-hydroxyethylthio)-16(S)-hydroxy-9-oxo                        -13-                                                             hydroxy prostaglandin A.sub.1                                                                trans-prostenoic acid methyl ester and the                                     corresponding                                                    methyl ester  11β-isomer                                                  (U.S. Pat. No. 3,950,406)                                                 240  15-deoxy-16-hydroxy-17-                                                                      11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-17-meth                        yl-13-                                                           methyl-prostaglandin A.sub.1                                                                 trans-prostenoic acid and the corresponding                                    11β-isomer                                                  Example 273                                                               241  15-deoxy-16-hydroxy-17-                                                                      ethyl 11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-1                        7-                                                               methyl prostaglandin A.sub.1                                                                 methyl-13-trans-prostenoate acid and the                                       corresponding                                                    ethyl ester (Example 274)                                                                    11β-isomer                                             242  15-deoxy-16-hydroxy                                                                          11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-13-tran                        s-                                                               prostaglandin A.sub.1                                                                        prostenoic acid and the corresponding 11β-isomer            (Example 275)                                                             243  15-deoxy-16-hydroxy-20-                                                                      11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-13,17-t                        rans-                                                            nor-17-trans-prosta-                                                                         prostadienoic acid and the corresponding                                       11β-isomer                                                  glandin A.sub.1 (Example 276)                                             244  nat.-16,16-trimethylene                                                                      nat.-methyl 11α-(2-hydroxyethylthio)-15α-hy                        droxy-9-oxo-                                                     prostaglandin A.sub.1                                                                        16,16-trimethylene-13-trans-prostenoate and the                  Methyl ester (Example 267)                                                                   corresponding 11β-isomer                               245  nat. 16,16-trimethylene                                                                      nat.-methyl 11α-(2-hydroxyethylthio)-15α-hy                        droxy-9-oxo-                                                     prostaglandin A.sub.2 methyl                                                                 16,16-trimethylene-5-cis,13-trans-prostadienoic acid                           and                                                              ester (Example 268)                                                                          the corresponding 11β-isomer                           246  nat.-16,16-trimethylene                                                                      nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-16,16-                                                      prostaglandin A.sub.2                                                                        trimethylene-5-cis,13-trans-prostadienoic acid and                             the                                                              (Example 269) corresponding 11β-isomer                               247  nat.-16,16-trimethylene                                                                      nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-16,16-                                                      prostaglandin A.sub.1                                                                        trimethylene-13-trans-prostenoic acid and the                    (Example 270) corresponding 11β-isomer                               248  nat.-16,16-trimethylene-                                                                     nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-16,16-tri-                                                  20-methyl prostaglandin                                                                      methylene-20-methyl-5-cis,13-trans-prostadienoic acid                          and                                                              A.sub.2 (Example 271)                                                                        the corresponding 11β-isomer                           249  nat.-16,16-trimethylene-                                                                     nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-16,16-tri-                                                  20-ethyl-prostaglandin                                                                       methylene-20-ethyl-5-cis,13-trans-prostadienoic acid                           and                                                              A.sub.2 (Example 272)                                                                        the corresponding 11β-isomer                           250  15-deoxy-16-hydroxy                                                                          11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-13-tran                        s-prostenoic                                                     prostaglandin A.sub.1 (U.S.                                                                  acid and the corresponding 11β-isomer                       Pat. No. 3,965,143)                                                       251  15-deoxy-16-hydroxy-16-                                                                      methyl-11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo-                        16-methyl,                                                       methyl prostaglandin A.sub.1 3                                                               13-trans-prostenoate acid and the corresponding                                11β-isomer                                                  methyl ester (U.S. Pat.                                                        No. 3,965,143)                                                            252  nat.-15-methyl                                                                               methyl-nat.-11α-(2-hydroxyethylthio)-15α-hy                        droxy-9-oxo-15-                                                  prostaglandin A.sub.1                                                                        methyl, 13-trans-prostenoate and the corresponding                             11β-isomer                                                  Methyl ester                                                              253  nat.-15-methyl-                                                                              methyl-nat.-11α-(2-hydroxyethylthio)-15α-hy                        droxy-9-oxo-15-                                                  prostaglandin A.sub.2                                                                        methyl-5-cis,13-trans-prostadienoate and the                                   corresponding                                                    Methyl ester  11β-isomer                                             254  nat.-16,16-dimethyl                                                                          nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-16,16-                                                      prostaglandin A.sub.2                                                                        dimethyl-5-cis,13-trans-prostadienoic acid and the                             corresponding 11β-isomer                               255  nat.-16(S)-methyl                                                                            nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-16(S)-methyl-                                               prostaglandin A.sub.2                                                                        5-cis,13-trans-prostadienoic acid and the                                      corresponding                                                                  11β-isomer                                             256  nat.-         nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-5-cis,13-                                                   prostaglandin A.sub.3                                                                        trans,17-trans-prostatrienoic acid and the                                     corresponding                                                    (Example 265) 11β-isomer                                             257  nat.-20-methyl                                                                               nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-20-methyl-5-                                                prostaglandin A.sub.2                                                                        cis,13-trans-prostadienoic acid and the corresponding                          11β-                                                        (Example 264) isomer                                                      258  nat.-20-ethyl nat.-11α-(2-hydroxyethylthio)-15α-hydroxy-9                        -oxo-20-ethyl-5-                                                 prostaglandin A.sub.2                                                                        cis,13-trans-prostadienoic acid and the corresponding                          11β-                                                        (Example 263) isomer                                                      259  erythro-16-hydroxy-                                                                          erythro-11α-(2-hydroxyethylthio)-15α,16-dih                        ydroxy-9-oxo-5-                                                  prostaglandin A.sub.2                                                                        cis,13-trans-prostadienoic acid and the corresponding                          11β-                                                        (Example 277) isomer                                                      260  threo-16-hydroxy                                                                             threo-11α-(2-hydroxyethylthio)-15α,16-dihyd                        roxy-9-oxo-5-cis,                                                prostaglandin A.sub.2                                                                        13-trans-prostadienoic acid and the corresponding                              11β-isomer                                                  (Example 278)                                                             261  erythro-16-methoxy-                                                                          erythro-11α-(2-hydroxyethylthio)-15α-hydrox                        y-9-oxo-16-                                                      prostaglandin A.sub.2                                                                        methoxy-5-cis,13-trans-prostadienoic acid and the                (Example 279) corresponding 11β-isomer                               262  threo-16-methoxy-                                                                            threo-11α-(2-hydroxyethylthio)-15α-hydroxy-                        9-oxo-16-methoxy-                                                prostaglandin A.sub.2                                                                        5-cis,13-trans-prostadienoic acid and the                                      corresponding                                                    (Example 280) 11β-isomer                                             __________________________________________________________________________

EXAMPLE 263 Preparation of nat.-20-ethyl prostaglandin A₂

A solution of nat.-20-ethyl-9-oxo-11α,15(S)-bis-(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadienoic acid [Patent No. 2,150,361 (West Germany, 1972)] in tetrahydrofuran containing 1.5 N hydrochloric acid is kept at ambient temperature for 70 hours. The solution is flooded with saturated sodium chloride and extracted several times with ether. The combined extracts are washed with water, dried with anhydrous magnesium sulfate and taken to dryness to afford the subject compound.

EXAMPLES 264-280

The prostaglandins E of the table below when treated in the manner of Example 263 furnish the corresponding prostaglandins A.

                                      TABLE 29                                     __________________________________________________________________________     Example                                                                             Starting Prostaglandins E                                                                         Product Prostaglandins A                               __________________________________________________________________________     264  nat.-20-methylprostaglandin-E.sub.2.sup.a                                                         nat.-20-methylprostaglandin-A.sub.2                    265  nat.-prostaglandin-E.sub.3 - E. J. Corey,                                                         nat.-prostaglandin-A.sub.3                                  et al. Journ. Amer. Chem. Soc., 93,                                            1490 (1971)                                                               266  prostaglandin-E.sub.2 - E. J. Corey, et                                                           dl-prostaglandin-A.sub.2                                    al., Journ. Amer. Chem. Soc., 91,                                              5675 (1969)                                                               267  nat. 16,16-trimethylene PGE.sub.1 methyl                                                          nat. 16,16-trimethylene PGA.sub.1 methyl ester              ester.sup.b                                                               268  nat. 16,16-trimethylene PGE.sub.2 methyl                                                          nat. 16,16-trimethylene PGA.sub.2 methyl ester              ester.sup.b                                                               269  nat. 16,16-trimethylene PGE.sub.2.sup.b                                                           nat. 16,16-trimethylene PGA.sub.2                      270  nat. 16,16-trimethylene PGE.sub.1.sup.b                                                           nat. 16,16-trimethylene PGA.sub.1                      271  nat. 16,16-trimethylene-20-methyl                                                                 nat. 16,16-trimethylene-20-methyl PGA.sub.2                 PGE.sub.2.sup.b                                                           272  nat. 16,16-trimethylene-20-ethyl                                                                  nat. 16,16-trimethylene-20-ethyl PGA.sub.2                  PGE.sub.2.sup.b                                                           273  11α,16-dihydroxy-17-methyl-9-oxo-                                                           16-hydroxy-17-methyl-9-oxo-10,13-trans-                     13-trans-prostenoic acid.sup.c                                                                    prostadienoic acid                                     274  ethyl 11α,16-dihydroxy-17-methyl-                                                           ethyl 16-hydroxy-17-methyl-9-oxo-10,13-trans-               9-oxo-13-trans-prostenoic acid.sup.c                                                              prostadienoate                                         275  11α,16-dihydroxy-9-oxo-13-trans-                                                            16-hydroxy-9-oxo-10,13-trans-prostadienoic acid             prostenoic acid.sup.c                                                     276  11α,16-dihydroxy-9-oxo-20-nor-13,17-                                                        16-hydroxy-9-oxo-20-nor-10,13-trans,17-trans-               trans,trans-prostadienoic acid.sup.c                                                              prostadienoic acid                                     277  erythro-11α,15α,16-trihydroxy-9-                                                      erythro-15α,16-dihydroxy-9-oxo-5-cis,10,13-t                             rans-                                                       oxo-5-cis,13-trans-prostadienoic                                                                  prostatrienoic acid                                         acid.sup.d                                                                278  threo-11α,15α,16-trihydroxy-9-oxo-                                                    threo-15α,16-dihydroxy-9-oxo-5-cis,10,13-tra                             ns-                                                         5-cis,13-trans-prostadienoic acid.sup. d                                                          prostatrienoic acid                                    279  erythro-11α,15α-dihydroxy-16-methoxy-                                                 erythro-15α-hydroxy-9-oxo-16-methoxy-5-cis,1                             0,13-                                                       9-oxo-5-cis,13-trans-prostadienoic                                                                trans-prostatrienoic acid                                   acid.sup.e                                                                280  threo-11α,15α-dihydroxy-16-methoxy-                                                   threo-15α-hydroxy-9-oxo-16-methoxy-5-cis,10,                             13-                                                         5-cis,13-trans-prostadienoic acid.sup.e                                                           trans-prostatrienoic acid                              __________________________________________________________________________      .sup.a D. van Dorp, Annal of the New York Academy of Sciences, Volume 180      181 (1971).                                                                    .sup.b W. German Patent No. 2,510,818 (March 14, 1974).                        .sup.c U.S. Pat. No. 3,950,406 (April 12, 1976).                               .sup.d Japan Patent No. J5 1008249 (Derivent 1783ox110) (July 7, 1974).        .sup.e Japan Patent No. J5 0070340 (Derivent 61314w137) (October 29,           1973).                                                                   

EXAMPLE 281 Preparation of 2-(6-carboxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one

To a stirred solution of 2.24 g. (10 mmols) of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one (U.S. Pat. No. 3,952,033) and 0.82 g (10.5 mmols) of β-mercaptoethanol in 50 ml of methanol is added 10.5 ml of N/1 sodium methoxide in methanol solution during 30 minutes at room temperature. After the addition the solution is stirred at room temperature for 1 hour and treated with 4.8 g of glacial acetic acid (80 mmols). The solution is concentrated to volume of 10 ml, treated with 30 ml of brine, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated.

The resulting residue is purified by column chromatography on silica gel with chloroform progressively enriched in ether and finally ether to provide an oil.

EXAMPLE 282 Preparation of Bis-Trimethylsilyl Derivative of 2-(6-carboxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one

To a stirred, ice-cold solution of 1.42 g (5.0 mmols) of 2-(6-carboxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one (Example 281) in 10 ml of pyridine is added 2.50 ml of hexamethyldisilazane followed by 1.25 ml of chlorotrimethylsilane. The resulting mixture is stirred at ambient temperature for 4 hours. The volatile materials are evaporated under vacuum, and the resulting residue is stirred with petroleum ether. The mixture is filtered through celite, and the filtrate is concentrated to give a light yellow liquid.

EXAMPLE 283 Preparation of 2-(6-carboxyhexyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one

In the manner of Example 281 a methanol solution of 2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-1-one [Prostaglandins, 3, 921 (1973)] and β-mercaptoethanol is treated with sodium methoxide solution, acidified, concentrated, and extracted to provide the subject compound as an oil.

EXAMPLE 283a Preparation of Bis-Trimethylsilyl Derivative of 2-(6-carboxyhexyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one

In the manner of Example 281a a solution of 2-(6-carboxyhexyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one (Example 282) in pyridine is treated with hexamethyldisilazane and chlorotrimethylsilane to provide the subject compound as a liquid.

EXAMPLE 284 Preparation of 2-(6-carboxymethoxy-2-cis-hexenyl)-4-methoxycyclopent-2-en-1-one

A stirred solution of 6.28 g (27.8 mmols) of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one (U.S. Pat. No. 3,952,033) and 7.6 ml of concentrated sulfuric acid is heated at reflux temperature for 40 hours. The solution is treated with 7.4 g of sodium carbonate, concentrated, and partitioned with ether-brine. The ether extract is washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue is distilled to provide a colorless liquid, b.p. 130°-134° (0.05 mm).

EXAMPLE 285 Preparation of 2-(6-carbomethoxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-on

To a stirred solution of 7.57 g (30 mmols) of 2-(6-carbomethoxy-2-cis-hexenyl)-4-methoxycyclopent-2-en-1-one (Example 283) and 2.46 g (31.5 mmols) of β-mercaptoethanol in 150 ml of methanol is added 15 ml of N/10 sodium methoxide in methanol solution. After 50 minutes at room temperature the solution is acidified with 0.27 ml of gl. acetic acid and partitioned with ether-brine. The ether extract is washed with brine, dried over magnesium sulfate, and concentrated. The residue is subjected to column chromatography on silica-gel to provide an oil.

EXAMPLE 286 Preparation of 2-(6-carbomethoxy-2-cis-hexenyl)-4-(2-trimethylsiloxyethylthio)cyclopent-2-en-1-one

To a stirred, ice-cold solution of 2.98 g (10 mmols) of 2-(6-carbomethoxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one (Example 283a) in 10 ml of pyridine is added 2.50 ml of hexamethyldisilazane followed by 1.25 ml of chlorotrimethylsilane. The resulting mixture is stirred at ambient temperature for 2.5 hours. The volatile materials are evaporated under vacuum, and the resulting residue is stirred with petroleum ether. The mixture is filtered through Celite, and the filtrate is concentrated to give a light yellow liquid.

EXAMPLE 287 Preparation of dl-methyl esters of 11-deoxy-11α-(2-hydroxyethylthio)-15α-prostaglandin E₂ and the 15β-isomer

To a stirred solution of 2.48 g (5.0 mmols) of 1-iodo-3-triphenylmethoxy-trans-1-octene (Tetrahedron Letters, 1975, 765) in 20 ml of ether at -78° is added 6.25 ml of 1.6 M t-butyllithium in pentane during 10 minutes. The solution is stirred at -78° for 1 hour, warmed to -45° during 15 minutes and recooled to -78°.

The above solution is treated during 10 minutes with a solution prepared from 653 mg (5.0 mmols) of copper pentyne, 2.1 ml of hexamethylphosphorous triamide, and 15 ml of ether, at a temperature of -78° to -70°. The resulting solution is stirred at -78° for 60 minutes and treated during 10 minutes with a solution of 1.48 g (4.0 mmols) of 2-(6-carbomethoxy-2-cis-hexenyl)-4-(2-hydroxyethylthio)cyclopent-2-en-1-one (Example 283b) in 10 ml of ether. After 10 minutes at -78° the solution is warmed to -45° during 10 minutes, maintained at -45° to -40° for 2 hours, recooled to -78°, and treated with a solution of 0.60 ml of gl. acetic acid in 10 ml of ether. The mixture is diluted with 100 ml of ether and poured into a stirred, ice-cold mixture of 50 ml of saturated ammonium chloride and 10 ml of 4 N hydrochloric acid. The ether phase is separated and washed successively with cold 2 N hydrochloric acid, water, and brine. The solution is dried over magnesium sulfate and concentrated.

The residue (3.24 g) is dissolved in a solution of 32 ml of gl. acetic acid, 16 ml of THF, and 8 ml of water, and the solution is heated at 45° for 6 hours and partitioned with half-saturated brine and ether. The ether phase is washed with brine, dried over magnesium sulfate, and concentrated.

The residue is subjected to dry column chromatography on silica gel with the solvent system 60:40:1 benzene-ethyl acetate-acetic acid to provide the more mobile epimer (11-deoxy-11α-(2-hydroxyethylthio)-15-epi-prostaglandin E₂,methyl ester) as a light yellow oil, and the more polar epimer (11-deoxy-11α-(2-hydroxyethylthio)-prostaglandin E₂,methyl ester) as a light yellow oil.

EXAMPLES 288-373

Treatment of ether cyclopentenone 282 or 283 with a lithio cuprate generated from the indicated vinyl iodide of Table 30 by the procedure described in Example 287 followed by chromatography is productive of the separated 15-hydroxy epimers and 16-hydroxy mixtures. When a vinylstannyl molecule is utilized, the lithiation is accomplished in tetrahydrofuran with n-butyllithium (l. equiv.) at -40° to -20° C. for 1-3 hours.

                                      TABLE 30                                     __________________________________________________________________________     Example                                                                             Starting Olefin                                                                          Starting Cyclopentenone                                                                    Separated Products                                  __________________________________________________________________________     288  13        282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-                                                                       16,16-trimethylene-5-cis,13-trans-prostadienoic                                O                                                                              acid and the 15β-epimer                        289  50        282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16,16-                                                                 trimethylene-20-methyl-5-cis,13-trans-prosta-                                  dienoic acid and the 15β-epimer                290  51        282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16,16-                                                                 trimethylene-20-ethyl-5-cis,13-trans-prostadien                                -                                                                              oic acid and the 15β-epimer                    291  194       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           vinyl-5-cis,13-trans-prostadienoic acid             292  192       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           cyclopropyl-5-cis,13-trans-prostadienoic acid       293  193       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           cyclopropyl-20-ethyl-5-cis,13-trans-prostadieno                                ic                                                                             acid                                                294  195       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           vinyl-20-ethyl-5-cis,13-trans-prostadienoic                                    acid                                                295  76        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .,16-di-                                                                       hydroxy-9-oxo-5-cis,13-trans-                                                  prostadienoic acid and the 15β-epimer          296  74        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .-hydroxy-9-                                                                   oxo-16-methoxy-5-cis,13-trans-prostadienoic                                    acid and the 15β-epimer                        297  77        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .-hydroxy-9-                                                                   oxo-16-ethoxy-5-cis,13-trans-prostadienoic                                     acid                                                                           and the 15β-isomer                             298  84        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .,16-di-                                                                       hydroxy-9-oxo-20-methyl-5-cis,13-trans-prosta-                                 e                                                                              dienoic acid and the 15β-epimer                299  85        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .,16-di-                                                                       hydroxy-9-oxo-20-ethyl-5-cis,13-trans-prosta-                                  dienoic acid and the 15β-epimer                300  87        282         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .,16-di-                                                                       hydroxy-9-oxo-5-cis,13-trans-17-trans-prosta-                                  trienoic acid and the 15β-epimer               301  69        282         threo-11α-(2-hydroxyethylthio)-15α                                 ,16-dihydroxy-                                                                 9-oxo-5-cis,13-trans-prostadienoic acid and                                    the 15β-epimer                                 302  89        282         threo-11α-(2-hydroxyethylthio)-15α,                                16-dihydroxy-                                                                  9-oxo-20-methyl-5-cis,13-trans-prostadienoic                                   acid and the 15β-epimer                        303  90        282         threo-11α-(2-hydroxyethylthio)-15α,                                16-dihydroxy-                                                                  9-oxo-20-ethyl-5-cis,13-trans-prostadienoic                                    acid and the 15β-isomer                        304  130       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           methyl-5-cis,13-trans-prostadienoic acid            305  107       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -5-cis,                                                                        13-trans-prostadienoic acid                         306  144       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -17-                                                                           methyl-5-cis,13-trans-prostadienoic acid            307  112       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -20-                                                                           methyl-5-cis,13-trans-prostadienoic acid            308  113       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -20-                                                                           ethyl-5-cis,13-trans-prostadienoic acid             309  139a      282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           methyl-20-ethyl-5-cis,13-trans-prostadienoic                                   acid                                                310  137       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16,20-                                                                        dimethyl-5-cis,13-trans-prostadienoic acid          311  139       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           methyl-5-cis,13-trans-17-trans-prostatrienoic                                  acid                                                312  151       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -17-                                                                           methyl-20-ethyl-5-cis,13-trans-prostadienoic                                   acid                                                313  152       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -5-cis,                                                                        13-trans-17-trans-prostatrienoic acid               314  153       282         11α-(2-hydroxyethylthio)-16(R)-hydroxy-9-                                oxo-5-                                                                         cis,13-trans-prostadienoic acid                     315  154       282         11α-(2-hydroxyethylthio)-16(S)-hydroxy-9-                                oxo-5-                                                                         cis,13-trans-prostadienoic acid                     316  148a      282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -20-                                                                           ethyl-5-cis,13-trans-17-trans-prostatrienoic                                   acid                                                317  1-iodo-3-tri-                                                                            282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-5-                                               phenylmethoxy-1-      cis,13-trans-prostadienoic acid and the                                        15β-                                                trans-octene          epimer                                                   (U.S. Pat. No.                                                                 3,873,607).                                                               318  1-iodo-3-tri-                                                                            282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-20-                                              phenylmethoxy-1-      methyl-5-cis,13-trans-prostadienoic acid and             trans-nonene          the 15β-epimer                                      (U.S. Pat. No.                                                                 3,873,607).                                                               319  1-iodo-3-tri-                                                                            282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-20-                                              phenylmethoxy-1-      ethyl-5-cis,13-trans-prostadienoic acid and         trans-decene   the 15β-epimer                                                  (U.S. Pat. No.                                                                 3,873,607).                                                               320  1-iodo-3-tri-                                                                            282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16,16-                                           phenylmethoxy-4,4-    dimethyl-5-cis,13-trans-prostadienoic acid                                     and                                                      dimethyl-1-trans-     the 15β-epimer                                      octene (U.S. Pat.                                                              No. 3,873,607).                                                           321  1-iodo-3-tri-                                                                            282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16-                                              phenylmethoxy-4-      methyl-5-cis,13-trans-prostadienoic acid and             methyl-1-trans-       the 15β-isomer                                      octene (U.S. Pat.                                                              No. 3,876,690).                                                           322  1-iodo-3-tri-                                                                            282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16-                                              phenylmethoxy-4-      ethyl-5-cis,13-trans-prostadienoic acid and              ethyl-1-trans-        the 15β-epimer                                      octene (U.S. Pat.                                                              No. 3,876,690).                                                           323  1-iodo-3-methyl-                                                                         282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-15-                                              3-trimethylsilyl-     methyl-5-cis,13-trans-prostadienoic acid and             oxy-trans-1-octene    the 15β-epimer                                      (Example 185)                                                             324  1-iodo-3-methyl-3-                                                                       282         11α -(hydroxyethylthio)-15α-hydroxy                                -9-oxo-15-                                               trimethylsilyloxy-    methyl-20-ethyl-5-cis,13-trans-prostadienoic             trans-1-decene        acid and the 15β-epimer                             (Example 190a)                                                            325  220       282         11α-(2-hydroxyethylthio)-15-hydroxy-9-oxo                                -15,19-                                                                        methylene-20-nor-5-cis,13-trans-prostadienoic                                  acid                                                326  221       282         11α-(2-hydroxyethylthio)-15-hydroxy-9-oxo                                -15,18-                                                                        methylene-19,20-dinor-5-cis,13-trans-prostadien                                -                                                                              oci acid and the 15β-epimer                    327  219       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16,20-                                                                        methylene-5-cis,13-trans-prostadienoic acid         328  222       282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16,19-                                                                        methylene-20-nor-5-cis,13-trans-prostadienoic                                  acid                                                329  216       282         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-15,16-                                                                 cis-trimethylene-5-cis,13-trans-prostadienoic                                  acid and the 15β-epimer                        330  139a      282         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -20-                                                                           ethyl-5-cis,13-trans-17-trans-prostatrienoic                                   acid                                                331  13        283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16,16-                                                                 trimethylene-13-trans-prostenoic acid and the                                  15β-epimer                                     332  50        283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16,16-                                                                 trimethylene-20-methyl-13-trans-prostenoic                                     acid and the 15β-epimer                        333  51        283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16,16-                                                                 trimethylene-20-ethyl-13-trans-prostenoic                                      acid                                                                           and the 15β-epimer                             334  194       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           vinyl-13-trans-prostenoic acid                      335  192       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           cyclopropyl-13-trans-prostenoic acid                336  193       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           cyclopropyl-20-ethyl-13-trans-prostenoic acid       337  195       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           vinyl-20-ethyl-13-trans-prostenoic acid             338  76        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                                . ,16-di-                                                                      hydroxy-9-oxo-13-trans-prostenoic acid and                                     the                                                                            15β-epimer                                     339  74        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .-hydroxy-9-                                                                   oxo-16-methoxy-13-trans-prostenoic acid and                                    the                                                                            15β-epimer                                     340  77        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .-hydroxy-9-                                                                   oxo-16-ethoxy-13-trans-prostenoic acid and                                     the                                                                            15β-isomer                                     341  84        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                                . ,16-dihydroxy-                                                               9-oxo-20-methyl-13-trans-prostenoic acid and                                   the 15β-epimer                                 342  85        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                                . ,16-dihydroxy-                                                               9-oxo-20-ethyl-13-trans-prostenoic acid and                                    the                                                                            15β-epimer                                     343  87        283         erythro-11α-(2-hydroxyethylthio)-15.alpha                                .,16-dihydroxy-                                                                9-oxo-13-trans-17-trans-prostadienoic acid                                     and                                                                            the 15β-epimer                                 344  69        283         threo-11α-(2-hydroxyethylthio)-15α-                                (2-hydroxyethylthio)-15α,16-dihydroxy-                                   9-oxo-13-trans-prostenoic acid and the                                         15β-epimer                                     345  89        283         threo-11α-(2-hydroxyethylthio)-15α,                                16-dihydroxy-                                                                  9-oxo-20-methyl-13-trans-prostenoic acid and                                   the                                                                            15β-epimer                                     346  90        283         threo-11α-(2-hydroxyethylthio)-15α,                                16-dihydroxy-                                                                  9-oxo-20-ethyl-13-trans-prostenoic acid and                                    the                                                                            15β-isomer                                     347  130       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           methyl-13-trans-prostenoic acid                     348  107       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -13-                                                                           trans-prostenoic acid                               349  144       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -17-                                                                           methyl-13-trans-prostenoic acid                     350  112       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -20-                                                                           methyl-3-trans-prostenoic acid                      351  113       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -20-                                                                           ethyl-13-trans-prostenoic acid                      352  139a      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           methyl-20-ethyl-13-trans-prostenoic acid            353  137       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16,20-                                                                        dimethyl-13-trans-prostenoic acid                   354  139       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16-                                                                           methyl-13-trans-17-trans-prostadienoic acid         355  151*      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -17-                                                                           methyl-20-ethyl-13-trans-prostenoic acid            356  152       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -13-                                                                           trans-17-trans-prostadienoic acid                   357  153       283         11α-(2-hydroxyethylthio)-16(R)-hydroxy-9-                                oxo-13-                                                                        trans-prostenoic acid                               358  154       283         11α-(2-hydroxyethylthio)-16(S)-hydroxy-9-                                oxo-13-                                                                        trans-prostenoic acid                               359  148a      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -20-                                                                           ethyl-13-trans-17-trans-prostadienoic acid          360  1-iodo-3-tri-                                                                            283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-13-                                              phenylmethoxy-1-      trans-prostenoic acid and the 15β-epimer            trans-octene                                                                   (U.S. Pat. No.                                                                 3,873,607).                                                               361  1-iodo-3-tri-                                                                            283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-20-                                              phenylmethoxy-1-      methyl-13-trans-prostenoic acid and the                                        15β-                                                trans-nonene (U.S.    epimer                                                   Pat. No. 3,873,607)                                                       362  1-iodo-3-tri-                                                                            283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-20-                                              phenylmethoxy-1-      ethyl-13-trans-prostenoic acid and the                                         15β-                                                trans-decene          epimer                                                   (U.S. Pat. No.                                                                 3,873,607).                                                               363  1-iodo-3-tri-                                                                            283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16,16-                                           phenylmethoxy-4,4-    dimethyl-13-trans-prostenoic acid and the                                      15β-                                                dimethyl-1-trans-     epimer                                                   octene (U.S. Pat.                                                              No. 3,873,607).                                                           364  1-iodo-3-tri-                                                                            283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16-                                              phenylmethoxy-4-      methyl-13-trans-prostenoic acid and the                                        15β-                                                methyl-1-trans-       isomer                                                   octene (U.S. Pat.                                                              No. 3,876,690).                                                           365  1-iodo-3-tri-                                                                            283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-16-                                              phenylmethoxy-4-      ethyl-13-trans-prostenoic acid and the                                         15β-                                                ethyl-1-trans-        epimer                                                   octene (U.S. Pat.                                                              No. 3,876,690).                                                           366  1-iodo-3-methyl-                                                                         283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-15-                                              3-trimethylsilyl-     methyl-13-trans-prostenoic acid and the                                        15β-                                                oxy-trans-1-octene    epimer                                                   (Example 190)                                                             367  1-iodo-3-methyl-                                                                         283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-                                                 3-trimethylsilyl-     15-methyl-20-ethyl-13-trans-prostenoic acid              oxy-trans-1-decene    and the 15β-epimer                                  (Example 190a)                                                            368  220       283         11α-(2-hydroxyethylthio)-15-hydroxy-9-oxo                                -15,19-                                                                        methylene-20-nor-13-trans-prostenoic acid           369  221       283         11α-(2-hydroxyethylthio)-15-hydroxy-9-oxo                                -15,18-                                                                        methylene-19,20-dinor-13-trans-prostenoic                                      acid                                                                           and the 15β-epimer                             370  219       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16,20-                                                                        methylene-13-trans-prostenoic acid                  371  222       283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -16,19-                                                                        methylene-20-nor-13-trans-prostenoic acid           372  216       283         11α-(2-hydroxyethylthio)-15α-hydrox                                y-9-oxo-15,16-                                                                 cis-trimethylene-13-trans-prostenoic acid and                                  the 15β-epimer                                 373  139a      283         11α-(2-hydroxyethylthio)-16-hydroxy-9-oxo                                -20-                                                                           ethyl-13-trans-17-trans-prostadienoic               __________________________________________________________________________                                acid                                           

EXAMPLE 374 Preparation of 1R,2R(and 1S,2S)-1-(trans-2-Iodovinyl)-1-trimethylsilyloxy-2-butylcyclopentane

To a mixture of 12.22 g of sodium borohydride and 60.82 g of 2-methyl-2-butene in 450 ml of tetrahydrofuran under nitrogen at 0° C., is added 54.6 ml of boron trifluoride etherate, dropwise over a 20 minute period. The solution is stirred at 0° C. for 2 hours and then at room temperature for 30 minutes. This solution is cooled to 0° C. and 55.5 g of 1R,2R(and 1S,2S)-1-ethynyl-1-trimethylsilyloxy-2-butylcyclopentane in 50 ml of tetrahydrofuran is added. The mixture is allowed to stand in a cold room overnight. To this mixture at 0° C. is added with stirring 112.8 g of trimethylamine oxide over a 20 minute period. The mixture is stirred at room temperature for 90 minutes and then filtered. To the filtrate is added simultaneously a solution of 565 g of sodium hydroxide in 2000 ml of water and a solution of 300 g of iodine in 300 ml of tetrahydrofuran. The mixture is stirred 30 minutes, the organic layer is separated and the aqueous layer is extracted with ether. The combined organic solutions are washed with saturated sodium thiosulfate solution and with saturated sodium chloride solution. The solution is dried with magnesium sulfate and filtered through a pad of silica gel. The solution is removed giving an orange liquid which is chromatographed on a dry column of silica gel giving 59.5 g of the product as a yellow liquid.

EXAMPLE 375 Preparation of 1-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethylsilyloxycyclohexane

To a stirred mixture of 31.5 g of 1-propargyl-1-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-n-butyltin hydride. The stirred mixture is heated to about 80° C. The initial exothermic reaction is moderated, and the temperature is subsequently maintained at 130°-135° C. for one hour.

The product is distilled to afford 56 g of colorless liquid, bp 150°-160° C. (0.15-0.3 mm), pmr (CDCl₃): 6.0 (multiplet, vinyl protons).

EXAMPLE 376 Preparation of 4-Oxo-1-iodo-trans-1-octene

To a stirred suspension of 6.15 g of pyridinium chlorochromate (Tetrahedron Letters, 1975, 2647) in 20 ml of methylene chloride is added 450 mg of sodium acetate. After 5 minutes a solution of 3.64 g of 4-hydroxy-1-iodo-trans-1-octene in 15 ml of methylene chloride is added in one portion. The dark mixture is stirred at room temperature for 75 minutes, diluted with 50 ml of ether, and decanted. The solid sludge is washed repeatedly with ether and decanted. The combined solutions are percolated through Florisil. The solution is concentrated to give an orange liquid, pmr spectrum (CDCl₃): 3.20 (d, j=7 cps, ═CHCH₂ CO).

EXAMPLE 377 Preparation of 4-Hydroxy-4-vinyl-1-iodo-trans-1-octene

To a stirred solution of 7.8 ml of vinyl magnesium chloride (2.3 M in tetrahydrofuran), at -25° C. is added a solution of 3.55 g of 4-oxo-1-iodo-trans-1-octene in 20 ml of tetrahydrofuran during 15 minutes. After the addition, the solution is stirred at -20° C. to -15° C. for 30 minutes. The reaction is quenched with a mixture of hexane and ice. The aqueous phase is separated and extracted with additional hexane. The combined hexane extracts are washed successively with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to dry column chromatography on silica gel with benzene as developing solvent to give a liquid, pmr spectrum (CDCl3): 5.2 (m, terminal CH₂), 5.83 (q, CH═CH₂), 6.13 (d, ICH═), and 6.52 (m, ICM═CH).

EXAMPLE 378 Preparation of E-1-Tri-n-butylstannyl-1-octene

A solution of 10.0 g (0.0908 mol) of 1-octyne, 60 ml of anhydrous toluene, 230 mg of azobisisobutylonitrile (AIBN), and 25 ml (0.0943 mol) of tri-n-butyltin hydride is refluxed under an argon atmosphere for 3 hours. The reaction mixture is cooled to ambient temperature and concentrated in vacuo. The resulting yellow liquid is distilled (bulb to bulb) to give 36.29 (99%) of the stannyl octene as a pale yellow liquid.

EXAMPLE 379 Preparation of dl-11,15-Bisdeoxy-11α-(2-hydroxyethylthio)-PGE₂ methyl ester C-13,14 cis isomer

To a stirred solution of 4.49 (0.0054 mol) of vinyl stannane and 12 ml of anhydrous tetrahydrofuran, cooled to -78° C. is slowly added 5.2 ml (0.0114 mol) of n-butyllithium. After 15 minutes, the reaction mixture is warmed to -15° C. for 11/2 hour, recooled to -78° Cl, and to it is added a solution of 1.70 g (0.0130 mol) of copper (I) pentyne, 7 ml of hexamethylphosphorous triamide (HMPTA), and 20 ml of anhydrous ether. After 1 hour, a solution of 2.0 g (0.00054 mol) of cyclopentenone 15 and 15 ml of anhydrous ether is added. The resulting solution is stirred at this temperature for 30 minutes, warmed to -30° C. for 2 hours, recooled to -78° C., and to it is added 5 ml of glacial acetic acid. The reaction mixture is poured into a saturated solution of ammonium chloride and is vigorously stirred for 30 minutes. The aqueous phase is separated and extracted with 150 ml of ether in 2 portions. The combined organic phases are washed with 5% hydrochloric acid solution and brine, and then concentrated in vacuo to give an amber oil. A solution of the oil in 140 ml of acetic acid-tetrahydrofuran-water (4:2:1) is stirred at ambient temperature for 1 hour, diluted with toluene, and concentrated in vacuo to give 6.1 g of amber oil. This oil is applied to a silica-gel dry column (3"×55"; 2:3/ethyl acetate:benzene+2% acetic acid; and 600 ml of eluant is collected).

The more polar isomer (13-cis) is isolated from the column at R_(f) 0.58-0.65 as 133 mg (6%) of a yellow oil.

The less polar isomer (13-trans) is isolated from the column at R_(f) 0.73-0.81 as 951 mg (43%) of a yellow oil.

EXAMPLE 380 Preparation of methyl nat. 9α,15α-dihydroxy-11α-(2-hydroxyethylthio)-5-cis,13-trans-prostadienoate

To a solution of 250 mg (0.59 mM) of methyl nat.-9-oxo-11α-(2-hydroxyethylthio)-15α-hydroxy-5-cis,13-trans-prostadienoate (Example 229) in 3 ml of dry tetrahydrofuran, stirred at -78° C. in an argon atmosphere, is added dropwise 1.3 ml (0.65 mM) of 0.5 M lithium perhydro-9b-boraphenalyl hydride (PBPH) in tetrahydrofuran. The solution is stirred for 40 minutes then quenched with 3 ml of water. Ethyl acetate (3 ml) is added and the mixture is removed from the bath and allowed to warm to ambient temperature. The aqueous phase is separated and washed several times with saturated sodium chloride solution, dried and taken to dryness. The resulting oil is applied to a dry column (11/4" flat) using 160 g of silica-gel and developed with ethyl acetate-benzene (100:1). The column is divided into 1/2" segments. Segments 12-26 are combined to furnish 204 mg (82%) of product as an oil.

EXAMPLE 381 Preparation of methyl nat. 9β,15α-dihydroxy-11α-(2-hydroxyethylthio)-5-cis,13-trans-prostadienoate

Reduction of 272 mg of methyl nat. 9-oxo-11β-(2-hydroxyethylthio)-15α-hydroxy-5-cis,13-trans-prostadienoate (Example 229) using 1.5 ml of PBPH according to the procedure described in Example 380 furnishes 438 mg of crude material. Dry column chromatography is described above gives 138 mg (51%) of oily product (located in segments 12-26).

EXAMPLE 382 Preparation and separation of nat. 9α,15α-dihydroxy-11α-(2-hydroxyethylthio)-13-trans-prostenoic acid and nat. 9β,15α-dihydroxy-11α-(2-hydroxyethylthio)-13-trans-prostenoic acid

To a stirred, ice-cold solution of nat. 11α-(2-hydroxyethylthio)-15α-hydroxy-9-oxo-13-trans-prostenoic acid (Example 228) in ethanol is added sodium borohydride in small portions. The mixture is stirred at 0° C. for 5 minutes and then at ambient temperature for 1 hour.

The bulk of the ethanol is evaporated at room temperature (in vacuo) and the residue is partitioned with cold diluted hydrochloric acid and ethyl acetate. The organic phase is separated and washed with water and brine, dried magnesium sulfate and concentrated. The residue is subjected to silica-gel chromatography to give the separated 9α and 9β isomers.

EXAMPLE 383

Treatment of the 9-oxo-11α-(2-hydroxyethylthio)prostanoic analogs of Examples 224-262 and 288-373 by the procedure of Example 380 is productive of the corresponding 9α-hydroxy-11α-(2-hydroxyethylthio)-prostanoic analogs.

EXAMPLE 384

Treatment of the 9-oxo-11β-(2-hydroxyethylthio)-prostanoic analogs of Examples 224-262 and 288-373 by the procedure of Example 381 is productive of the corresponding 9β-hydroxy-11β-(2-hydroxyethylthio)-prostanoic analogs.

EXAMPLE 385

Treatment of the 9-oxo-11α-(2-hydroxyethylthio)-prostanoic analogs of Examples 223-262 and 288-373 by the sodium borohydride procedure of Example 382, followed by silica-gel chromatography, is productive of the corresponding 9α-hydroxy-11α-(2-hydroxyethylthio) and 9β-hydroxy-11α-(2-hydroxyethylthio)-prostanoic analogs.

EXAMPLE 386

Treatment of the 9-oxo-11β-(2-hydroxyethylthio)-prostanoic analogs of Example 223-262 and 288-373 by the sodium borohydride procedure of Example 382, followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(2-hydroxyethylthio) and 9β-hydroxy-11β-(2-hydroxyethylthio)-prostanoic analogs.

EXAMPLE 387

Treatment of 9-oxo-15α-hydroxy-5-trans, 10, 13-trans-prostatrienoic acid with β-mercapto-ethanol by the procedure of Example 229 followed by silica-gel chromatography is productive of 9-oxo-11α-(2-hydroxyethylthio) 15α-hydroxy-5-trans, 13-trans prostadienoic acid and 9-oxo-11β(α-hydroxyethylthio)-15α-hydroxy-5-trans, 13-trans-prostadienoic acid.

EXAMPLE 388

Treatment of the 9-oxo-1,15α-dihydroxy-5-cis, 10, 13,-trans-prostatriene with β-mercaptoethanol by the procedure of Example 229 followed by silica-gel chromatography is productive of 9-oxo-11α-(2-hydroxyethylthio)-1,5α-dihydroxy-5-cis, 13-trans-prostadiene and 9-oxo-11β-(2-hydroxyethylthio)-1,15α-dihydroxy-5-cis, 13-trans-prostadiene.

EXAMPLE 389

Treatment of the 9-oxo-15α-hydroxy-16-(R)-methyl-5-cis, 10, 13-trans-prostatrienoic acid with β-mercaptoethanol by the procedure of Example 229 followed by silica-gel chromatography is productive of 9-oxo-11α(2-hydroxyethylthio)-15α-hydroxy-16(R)-methyl-5-cis, 13-trans-prostadien-1-al and 9-oxo-11β-(2-hydroxyethylthio)-15α-hydroxy-16(R)-methyl-5-cis, 13-trans prostadien-1-al.

EXAMPLE 390

Treatment of 9-oxo-16(S)-methyl-20-methoxy-5-cis 10, 13-trans-prostatrienoic acid (EXAMPLE 469) with β-mercaptoethanol by the procedure of Example 229 followed by silica-gel chromatography is productive of 9-oxo-11α(2-hydroxyethylthio)-15α-hydroxy-16(S)-methyl-20-methoxy-5-cis, 13-trans-prostadienoic acid and 9-oxo-11β(2-hydroxyethylthio)-15-α-hydroxy-16(S)-methyl-20-methoxy-5-cis, 13-trans-prostadienoic acid.

EXAMPLE 391

Treatment of the 5,6-didehydro PGA₁ (U.S. Pat. No. 3,883,574) with β-mercaptoethanol by the procedure of Example 229 followed by silica-gel chromatography is productive of 9-oxo-11α(2-hydroxyethylthio)-15α-hydroxy-13-trans-prosten-5-yn-oic acid and 9-oxo-11β(2-hydroxyethylthio)15α-hydroxy-13-trans-prosten-5-yn-oic acid.

EXAMPLE 392

Treatment of 9-oxo-152α-hydroxy-4-cis, 10, 13-trans-prostatrienoic acid (Netherlands Pat. No. 7305434) with β-mercaptoethanol by the procedure of Example 229 followed by silica-gel chromatography is productive of 9-oxo-11α(2-hydroxyethylthio)15α-hydroxy-4-cis, 13-trans-prostadienoic acid and 9-oxo-11β-(2-hydroxyethylthio)-15α-hydroxy-4-cis, 13-trans-prostadienoic acid.

EXAMPLE 393

Treatment of the A-type prostaglandins of Table 31 with β-mercaptoethanol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(2-hydroxyethylthio)- and 11β-(2-hydroxyethylthio)-prostaglandins of the E type.

TABLE 31*

nat.-prostaglandin A₂ methyl ester

nat.-prostaglandin A₁

prostaglandin A₁

nat.-prostaglandin A₂

prostaglandin A₂

15-deoxy-16-hydroxy prostaglandin A₁ ethyl ester (U.S. Pat. No. 3,950,406)

15-deoxy-16-hydroxy prostaglandin A₁ methyl ester (U.S. Pat. No. 3,950,406)

15-deoxy-16-hydroxy-17-methyl-19,20-dinor prostaglandin A₁ (U.S. Pat. No. 3,950,406)

15-deoxy-16-hydroxy-17-ethyl-20-nor prostaglandin A₁ (U.S. Pat. No. 3,950,406)

nat.-15-deoxy-16(R)-hydroxy prostaglandin A₁ methyl ester (U.S. Pat. No. 3,950,406)

nat.-15-deoxy-16(S)-hydroxy prostaglandin A₁ methyl ester (U.S. Pat. No. 3,950,406)

15-deoxy-16-hydroxy-17-methyl-prostaglandin A₁ (Example 273)

15-deoxy-16-hydroxy-17-methyl prostaglandin A₁ ethyl ester (Example 274)

15-deoxy-16-hydroxy-prostaglandin A₁ ethyl ester (Example 275)

15-deoxy-16-hydroxy-20-nor-17-trans-prostaglandin A₁ (Example 276)

nat.-16,16-trimethylene prostaglandin A₁ Methyl ester (Example 267)

nat. 16,16-trimethylene prostaglandin A₂ metyl ester (Example 268)

nat.-16,16-trimethylene prostaglandin A₂ (Example 269)

nat.-16,16-trimethylene prostaglandin A₁ (Example 270)

nat.-16,16-trimethylene-20-methyl prostaglandin A₂ (Example 271)

nat.-16,16-trimethylene-20-ethyl-prostaglandin A₂ (Example 272)

15-deoxy-16-hydroxy prostaglandin A₁

nat.-16,16-dimethyl prostaglandin A₂

nat.-16(S)-methyl prostaglandin A₂

nat.-prostaglandin A₃ (Example 265)

nat.-20-methyl prostaglandin A₂ (Example 263)

nat.-20-ethyl prostaglandin A₂ (Example 263)

erythro-16-hydroxy-prostaglandin A₂ (Example 277)

threo-16-hydroxy prostaglandin A₂ (Example 278)

erythro-16-methoxy-prostaglandin A₂ (Example 279)

threo-16-methoxy-prostaglandin A₂ (Example 280)

15-deoxy-16-hydroxy-16-methyl prostaglandin A₁ methyl ester (U.S. Pat. No. 3,965,143)

nat.-15-methyl prostaglandin A₁ methyl ester

nat.-15-methyl prostaglandin A₂ Methyl ester

nat.-15-methyl-prostaglandin A₂ Methyl ester

16,16-trimethylene-17-phenyl-18,19,20-trinor-PGA₂

16,16-trimethylene-17-phenyl-18,19,20-trinor-PGA₁

16-p-fluorophenoxy-17,20-tetranor PGA₂ (Bel. Pat. No. 806995)

16-m-trifluoromethylphenoxy-17,20-tetranor PGA₂ (Bel. Pat. No. 805995)

16-m-chlorophenoxy-17,20-tetranor-PGA₂ (Bel. Pat. No. 806995)

16-phenoxy-17,20-tetranor-PGA₂ (Bel. Pat. No. 806995)

15-deoxy-16-hydroxy-16-vinyl-PGA₂

15-deoxy-16-hydroxy-16-vinyl-PGA₁

nat.-9-oxo-15α-hydroxy-5-trans 10, 13-trans-prostatrienoic acid (U.S. Pat. No. 3,759,978)

9-oxo-1,15α-dihydroxy-5-cis 10, 13-trans,-prostatriene

9-oxo-1,15α-dihydroxy-10,13-trans-prostadiene

9-oxo-15α-hydroxy-16(S)-methyl-2-trans, 10, 13-trans-prostatrienoic acid

9-oxo-15α-hydroxy-16(S)-methyl-20 methoxy-5-cis-10, 13-trans prostadienoic acid (Example 464)

9-oxo-15α-hydroxy-16(R)-methyl-5-cis-10, 13-trans-prostatrien-1-al (Example 463)

2-descarboxy-2[tetrazol-5-yl]-9-oxo-15α-hydroxy-5-cis, 10, 13-trans prostatrienoic acid(U.S. Pat. No. 3,883,513)

2-descarboxy-2[tetrazol-5-yl]-9-oxo-15α-hydroxy-10, 13-trans prostadienoic acid(U.S. Pat. No. 3,885,513)

2-descarboxy-2[tetrazol-5-yl]-9-oxo-15α-hydroxy-10, 13-trans-prostadienoic acid(U.S. Pat. No. 3,883,513)

N-Acetyl-PGA₂ carboxamide(U.S. Pat. No. 3,954,741)

N-Methanesulfonyl PGA₂ carboxamide(U.S. Pat. No. 3,954,741)

N-cycloprpylcarbonyl-PGA₂ carboxamide(U.S. Pat. No. 3,954,471)

N-cyclopropylcarbonyl-PGA₁ carboxamide(U.S. Pat. No. 3,954,741)

9-oxo-15α-hydroxy-16(R)-methyl-5-cis-10, 13-trans-prostatrien-1-al

trans-Δ² -PGA₁ (U.S. Pat. No. 4,024,174)

15-methyl-trans-Δ² -PGA₁ (U.S. Pat. No. 4,024,174)

15,16-dimethyl-trans-Δ² -PGA₁ (U.S. Pat. No. 4,024,174)

16-cyclohexyl-w-trinor-trans-Δ² -PGA₁ (U.S. Pat. No. 4,024,174)

trans-Δ² -PGA₂ methyl ester(U.S. Pat. No. 4,024,174)

15-methyl-trans-Δ² -PGA₂ methyl ester(U.S. Pat. No. 4,024,174)

16(R)-methyl-trans-Δ² -PGA₂ methyl ester(U.S. Pat. No. 4,024,174)

17-methyl-trans-Δ² -PGA₂ methyl ester (U.S. Pat. No. 4,024,174)

15,16-dimethyl-trans-Δ² -PGA₁ methyl ester(U.S. Pat. No. 4,024,174)

16-cyclohexyl-W-trinor-trans-Δ² -PGA₂ methyl ester (U.S. Pat. No. 4,024,174)

The ester of PGA₂ and 1-benzamido-4-hydroxynaphthalene (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and 1-acetamido-4-hydroxynaphthalene (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and p-hydroxyphenylurea (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and N-benzoyl-L-tyrosinamide (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and 1-hydroxy-4-ureidonaphthalene (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and phenol (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and 2-naphthol (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and p-acetamidophenol (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and hydroquinone benzoate (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and 2,4-diacetamidophenol (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and p-hydroxybenzoic acid, methyl ester (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and p-hydroxybenzamide (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and N-acetyl-L-tyrosinamide (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and p-tritylphenol (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and p-(p-benzamidobenzamido) (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and p-hydroxy-1,3-diphenylurea (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and N-(p-tritylphenyl)-p-hydroxybenzamide (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and hydroquinone, p-acetamidobenzoic acid ester (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and 1-hydroxy-5-naphthalenesulfonamide (U.S. Pat. No. 3,932,486)

The ester of pGA₂ and p-hydroxyacetophenone (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and p-hydroxybenzophenone (U.S. Pat. No. 3,932,486)

The ester of PGA₂ and o-hydroxybenzamide (U.S. Pat. No. 3,932,186)

The ester of PGA₁ and p-acetamidophenol (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and p-(p-acetamidobenzamidophenol) (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and p-(p-benzamidobenzamidophenol) (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and p-hydroxy-1,3-diphenylurea (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and p-phenylphenol (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and hydroquinone benzoate (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and hydroquinone, p-acetamidobenzoic acid ester (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and 2,4-diacetamidophenol (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and 1-acetamido-4-hydroxynaphthalene (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and 1-benzamido-4-hydroxynaphthalene (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and 1-hydroxy-4-uriedo naphthalene (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and 1-hydroxy-5-naphthalenesulfonamide (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and p-trityl phenol (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and N-acetyl-L-tyrosinamide (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and N-benzoyl-L-tyrosinamide (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and p-hydroxy benzaldehyde semicarbazone (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and p-hydroxybenzophenone (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and O-hydroxybenzamide (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and N-(p-tritylphenyl)-p-hydroxybenzamide (U.S. Pat. No. 3,948,970)

The ester of PGA₁ and p-hydroxy benzoic acid, methyl ester (U.S. Pat. No. 3,948,970)

The p-phenylphenacyl ester of PGA₁ (Bel. Pat. No. 832,458)

The p-phenylphenacyl ester of PGA₂ (Bel. Pat. No. 832,458)

The p-benzamidophenacyl ester of PGA₁ (Bel. Pat. No. 832,458)

The p-benzamidophenacyl ester of PGA₂ (Bel. Pat. No. 832,458)

The serine ester of PGA₂ (Japan Kokai No. 74,109,341) Chem. Abst., 27690a (1973)

The serine ester of PGA₁ (Japan Kokai No. 74,109,341) Chem. Abst. 27690a (1973)

The 4-carboxybutyl ester of PGA₂ (U.S. Pat. No. 3,857,831)

The 2-cyclohexylethyl ester of PGA₁ (Japan Kokai No. 74,25658) Chem. Abst. 170198f (1974)

The -2-glyceryl ester of PGA₂ (U.S. Pat. No. 3,632,627)

The 2-glyceryl ester of PGA₁ (U.S. Pat. No. 3,632,627)

The tyrosine amide of PGA₂ (Japan Kokai No. 75,52047) Chem. Abst., 147202q (1975)

EXAMPLE 394

Treatment of the A-type prostaglandins of Table 31 with 1,2-ethanedithiol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(2-mercaptoethanethio) and 11-deoxy-11β-(2-mercaptoethanethio) prostaglandins of the E-type.

EXAMPLE 395

Treatment of the A-type prostaglandins of Table 31 with 3-mercaptopropanol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(3-hydroxypropanethio) and 11-deoxy-11β-(3-hydroxypropanethio) prostaglandins of the E-type.

EXAMPLE 396

Treatment of the A-type prostaglandins of Table 31 with 1,3-propanedithiol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(3-mercaptopropanethio) and 11-deoxy-11β-(3-mercaptopropanethio) prostaglandins of the E-type.

EXAMPLE 397

Treatment of the A-type prostaglandins of Table 31 with 3-mercaptopropan-2-ol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(2-hydroxypropanthiol) and 11-deoxy-11β-(2-hydroxypropanethiol) prostaglandins of the E-type.

EXAMPLE 398

Treatment of the A-type prostaglandins of Table 31 with 2,3-dimercaptopropan-1-ol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(3-hydroxy-2-mercaptopropanethiol) and 11-deoxy-11β-(3-hydroxy-2-mercaptopropanethiol) prostaglandins of the E-type.

EXAMPLE 399

Treatment of the A-type prostaglandins of Table 31 with 3-mercapto-1,2-dihydroxypropane by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(2,3-dihydroxypropanethiol) and 11-deoxy-11β-(2,3-dihydroxypropanethiol) prostaglandins of the E-type.

EXAMPLE 400

Treatment of the A-type prostaglandins of Table 31 with propanethiol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-propanethiol and 11-deoxy-11β-propanethiol prostaglandins of the E-type.

EXAMPLE 401

Treatment of the A-type prostaglandins of Table 31 with mercaptoethane by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-ethanethiol and 11-deoxy-11β-ethanethiol prostaglandins of the E-type.

EXAMPLE 402

Treatment of the A-type prostaglandins of Table 31 with 1-mercaptoheptan-2-ol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(2-hydroxyheptanethiol) and 11-deoxy-11β-(2-hydroxyheptanethiol) prostaglandins of the E-type.

EXAMPLE 403

Treatment of the A-type prostaglandins of Table 31 with o-thiophenol by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(o-hydroxythiophenol) and 11-deoxy-11β-(o-hydroxythiophenol) prostaglandins of the E-Type.

EXAMPLE 404

Treatment of the A-type prostaglandins of Table 31 with 1-mercaptoacetic acid by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(1-carboxymethanethiol) and 11-deoxy-11β-(1-carboxymethanethiol) prostaglandins of the E-type.

EXAMPLE 405

Treatment of the A-type prostaglandins of Table 31 with 1-mercaptoethylacetate by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(α-carbethoxymethylethio) and 11-deoxy-11β-(α-carbethoxymethylethio) prostaglandins of the E-type.

EXAMPLE 406

Treatment of the A-type prostaglandins of Table 31 with 1-dimethylamino-2-mercaptoethane by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(2-dimethylaminoethanethio) and 11-deoxy-11β-(2-dimethylaminoethanethio) prostaglandins of the E-type.

EXAMPLE 407

Treatment of the A-type prostaglandins of Table 31 with 1-diethylamino-2-mercaptoethane by the procedure of Example 229 followed by silica-gel chromatography is productive of the correspondingly substituted 11-deoxy-11α-(2-diethylaminoethanethio) and 11-deoxy-11β-(2-diethylaminoethanethio) prostaglandins of the E-type.

EXAMPLE 408

Treatment of the 11-deoxy-11α-(2-hydroxyethylthio) prostaglandin of the E-type of Example 393 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(2-hydroxyethylthio) prostanoic analogs.

EXAMPLE 409

Treatment of the 11-deoxy-11β-(2-hydroxyethylthio) prostaglandin of the E-type of Example 393 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(2-hydroxyethylthio) prostanoic analogs.

EXAMPLE 410

Treatment of the 11-deoxy-11α-(2-mercaptoethanethiol) prostaglandin of the E-type of Example 391 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(2-mercaptoethanethiol) prostanoic analogs.

EXAMPLE 411

Treatment of the 11-deoxy-11β-(2-mercaptoethanethiol)-prostaglandin of the E-type of Example 391 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxyl-11β-(2-mercaptoethanethiol) prostanoic analogs.

EXAMPLE 412

Treatment of the 11-deoxy-11α-(3-hydroxypropanethiol)-prostaglandin of the E-type of Example 395 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(3-hydroxypropanethiol) prostanoic analogs.

EXAMPLE 413

Treatment of the 11-deoxy-11β-(3-hydroxypropanethiol) prostaglandin of the E-type of Example 395 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(3-hydroxypropanethiol) prostanoic analogs.

EXAMPLE 414

Treatment of the 11-deoxy-11α-(3-mercaptopropanethiol) prostaglandin of the E-type of Example 396 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(3-mercaptopropanethiol) prostanoic analogs.

EXAMPLE 415

Treatment of the 11-deoxy-11β-(3-mercaptopropanethiol) prostaglandin of the E-type of Example 396 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(3-mercaptopropanethiol) prostanoic analogs.

EXAMPLE 416

Treatment of the 11-deoxy-11α-(2-hydroxypropanethiol) prostaglandin of the E-type of Example 397 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(2-hydroxypropanethiol) prostanoic analogs.

EXAMPLE 417

Treatment of the 11-deoxy-11β-(2-hydroxypropanethiol) prostaglandin of the E-type of Example 397 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(2-hydroxypropanethiol) prostanoic analogs.

EXAMPLE 418

Treatment of the 11-deoxy-11α-(3-hydroxy-2-mercaptopropanethiol) prostaglandin of the E-type of Example 398 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(3-hydroxy-2-mercaptopropanethiol) prostanoic analogs.

EXAMPLE 419

Treatment of the 11-deoxy-11β-(3-hydroxy-2-mercaptopropanethiol) prostaglandin of the E-type of Example 398 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(3-hydroxy-2-mercaptopropanethiol) prostanoic analogs.

EXAMPLE 420

Treatment of the 11-deoxy-11α-(2,3-dihydroxypropanethiol) prostaglandin of the E-type of Example 399 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(2,3-dihydroxypropanethiol) prostanoic analogs.

EXAMPLE 421

Treatment of the 11-deoxy-11β-(2,3-dihydroxypropanethiol) prostaglandin of the E-type of Example 399 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(2,3-dihydroxypropanethiol) prostanoic analogs.

EXAMPLE 422

Treatment of the 11-deoxy-11α-(propanethiol) prostaglandin of the E-type of Example 400 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(propanethiol) prostanoic analogs.

EXAMPLE 423

Treatment of the 11-deoxy-11β(propanethiol) prostaglandin of the E-type of Example 400 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(propanethiol) prostanoic analogs.

EXAMPLE 424

Treatment of the 11-deoxy-11α-(ethanethiol) prostaglandin of the E-type of Example 401 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(ethanethiol) prostanoic analogs.

EXAMPLE 425

Treatment of the 11-deoxy-11β-(ethanethiol) prostaglandin of the E-type of Example 401 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(ethanethiol) prostanoic analogs.

EXAMPLE 426

Treatment of the 11-deoxy-11α-(2-hydroxyheptanethiol) prostaglandin of the E-type of Example 402 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(2-hydroxyheptanethiol) prostanoic analogs.

EXAMPLE 427

Treatment of the 11-deoxy-11β-(2-hydroxyheptanethiol) prostaglandin of the E-type of Example 402 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(2-hydroxyheptanethiol) prostanoic analogs.

EXAMPLE 428

Treatment of the 11-deoxy-11α-(o-hydroxythiolphenol) prostaglandin of the E-type of Example 403 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(o-hydroxythiophenol) prostanoic analogs.

EXAMPLE 429

Treatment of the 11-deoxy-11β-(o-hydroxythiophenol) prostaglandin of the E-type of Example 403 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(o-hydroxythiophenol) prostanoic analogs.

EXAMPLE 430

Treatment of the 11-deoxy-11α-(1-carboxymethanethiol) prostaglandin of the E-type of Example 404 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(1-carboxymethanethiol) prostanoic analogs.

EXAMPLE 435

Treatment of the 11-deoxy-11β-(2-dimethylaminoethanethiol) prostaglandin of the E-type of Example 406 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(2-dimethylaminoethanethiol) prostanoic analogs.

EXAMPLE 436

Treatment of the 11-deoxy-11α-(2-diethylaminoethanethiol) prostaglandin of the E-type of Example 407 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(2-diethylaminoethanethiol) prostanoic analogs.

EXAMPLE 437

Treatment of the 11-deoxy-11β-(2-diethylaminoethanethiol) prostaglandin of the E-type of Example 407 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(2-diethylaminoethanethiol) prostanoic analogs.

EXAMPLE 438

Treatment of the 11-deoxy-11α-(2-hydroxyethylthio) prostaglandins of the E-type of Example 393 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(2-hydroxyethylthio), and 9β-hydroxy-11α-(2-hydroxygethylthio) prostanoic analogs.

EXAMPLE 435

Treatment of the 11-deoxy-11β-(2-dimethylaminoethanethiol) prostaglandin of the E-type of Example 406 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(2-dimethylaminoethanethiol) prostanoic analogs.

EXAMPLE 436

Treatment of the 11-deoxy-11α-(2-diethylaminoethanethiol) prostaglandin of the E-type of Example 407 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 386 is productive of the corresponding 9α-hydroxy-11α-(2-diethylaminoethanethiol) prostanoic analogs.

EXAMPLE 437

Treatment of the 11-deoxy-11β-(2-diethylaminoethanethiol) prostaglandin of the E-type of Example 407 with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 387 is productive of the corresponding 9β-hydroxy-11β-(2-diethylaminoethanethiol) prostanoic analogs.

EXAMPLE 438

Treatment of the 11-deoxy-11α-(2-hydroxyethylthio) prostaglandins of the E-type of Example 393 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(2-hydroxyethylthio), and 9β-hydroxy-11α-(2-hydroxyethylthio) prostanoic analogs.

EXAMPLE 443

Treatment of the 11-deoxy-11β-(3-hydroxygpropanethio) prostaglandins of the E-type of Example 395 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(3-hydroxypropanethio), 9β-hydroxy-11β-(3-hydorxypropanethio) prostanoic analogs.

EXAMPLE 444

Treatment of the 11-deoxy-11α-(3-mercaptopropanethio) prostaglandin of the E-type of Example 396 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(3-mercaptopropanethio), 9β-hydroxy-11α(3-mercaptopropanethio) prostanoic analogs.

EXAMPLE 445

Treatment of the 11-deoxy-11β-(3-mercaptopropanethio) prostaglandin of the E-type of Example 396 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(3-mercaptopropanethio), 9β-hydroxy-11β(3-mercaptopropanethio) prostanoic analogs.

EXAMPLE 446

Treatment of the 11-deoxy-11α-(2-hydroxypropanethio) prostaglandin of the E-type of Example 397 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(2-hydroxypropanethio), 9β-hydroxy-11α-(2-hydroxypropanethio) prostanoic analogs.

EXAMPLE 447

Treatment of the 11-deoxy-11β-(2-hydroxypropanethio) prostaglandin of the E-type of Example 397 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(2-hydroxypropanethio), 9β-hydroxy-11β-(2-hydroxypropanethio) prostanoic analogs.

EXAMPLE 448

Treatment of the 11-deoxy-11α-(3-hydroxy-2-mercaptopropanethiol) prostaglandin of the E-type of Example 398 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(3-hydroxy-2-mercaptopropanethiol), 9β-hydroxy-11α-(3-hydroxy-2-mercaptopropanethiol) and prostanoic analogs.

EXAMPLE 449

Treatment of the 11-deoxy-11β-(3-hydroxy-2-mercaptopropanethiol) prostaglandin of the E-type of Example 398 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(3-hydroxy-2-mercaptopropanethiol) and 9β-hydroxy-11β-(3-hydroxy-2-mercaptopropanethiol) prostanoic analogs.

EXAMPLE 450

Treatment of the 11-deoxy-11-α-(2,3-dihydroxypropanethiol) prostaglandin of the E-type of Example 399 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(2,3-dihydroxypropanethiol) and 9β-hydroxy-11α-(2,3-dihydroxypropanethiol) prostanoic analogs.

EXAMPLE 451

Treatment of the 11-deoxy-11β-(2,3-dihydroxypropanethiol) prostaglandin of the E-type of Example 399 with sodium borohydride by the procedure of Exampoe 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(2,3-dihydroxypropanethiol) and 9β-hydroxy-11β-(2,3-dihydroxypropanethiol) prostanoic analogs.

EXAMPLE 452

Treatment of the 11-deoxy-11α-propanethiol prostaglandin of the E-type of Example 400 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-propanethiol and 9β-hydroxy-11α-propanethiol prostanoic analogs.

EXAMPLE 453

Treatment of the 11-deoxy-11β-propanethiol prostaglandin of the E-type of Example 400 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-propanethiol and 9-β-hydroxy-11β-propanethiol prostanoic analogs.

EXAMPLE 454

Treatment of the 11-deoxy-11α-ethanethiol prostaglandin of the E-type of Example 401 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-ethanethiol and 9β-hydroxy-11α-ethanethiol prostanoic analogs.

EXAMPLE 455

Treatment of the 11-deoxy-11β-ethanethiol prostaglandin of the E-type of Example 401 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-ethanethiol and 9β-hydroxy-11β-ethanethiol prostanoic analogs.

EXAMPLE 456

Treatment of the 11-deoxy-11α-(2-hydroxyheptanethiol) prostaglandin of the E-type of Example 402 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(2-hydroxyheptanethiol) and 9β-hydroxy-11α-(2-hydroxyheptanethiol) prostanoic analogs.

EXAMPLE 457

Treatment of the 11-deoxy-11β-(2-hydroxyheptanethiol) prostaglandin of the E-type of Example 402 with sodium borohydride by the procedure of Exampel 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(2-hydroxyheptanethiol) and 9β-hydroxy-11β-(2-hydroxyheptanethiol) prostanoic analogs.

EXAMPLE 458

Treatment of the 11-deoxy-11-α-(O-hydroxythiophenol) prostaglandin of the E-type of Example 403 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(o-hydroxythiophenol) and 9β-hydroxy-11α-(o-hydroxythiophenol) prostanoic analogs.

EXAMPLE 459

Treatment of the 11-deoxy-11β-(o-hydroxythiolphenol) prostaglandin of the E-type of Example 403 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(o-hydroxythiophenol) and 9β-hydroxy-11β-(o-hydroxythiophenol) prostanoic analogs.

EXAMPLE 460

Treatment of the 11-deoxy-11α-(carboxymethanethiol) prostaglandin of the E-type of Example 404 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(carboxymethanethiol) and 9-β-hydroxy-11α-(carboxymethanethiol) prostanoic analogs.

EXAMPLE 461

Treatment of the 11-deoxy-11β-(carboxymethanethio) prostaglandin of the E-type of Example 404 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(carboxymethanethio) and 9β-hydroxy-11β-(carboxymethanethio) prostanoic analogs.

EXAMPLE 462

Treatment of the 11-deoxy-11α-(carbethoxymethanethio) prostaglandin of the E-type of Example 405 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(carbethoxymethanethio) and 9β-hydroxy-11α-(carbethoxymethanethio) prostanoic analogs.

EXAMPLE 463

Treatment of the 11-deoxy-11β-(carbethoxymethanethio) prostaglandin of the E-type of Example 405 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(carbethoxymethanethio) and 9β-hydroxy-11β-(carbethoxymethanethio) prostanoic analogs.

EXAMPLE 464

Treatment of the 11-deoxy-11α-(2-dimethylaminoethanethio) prostaglandin of the E-type of Example 406 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(2-dimethylaminoethanethio) and 9β-hydroxy-11α-(2-dimethylaminoethanethio) prostanoic analogs.

EXAMPLE 465

Treatment of the 11-deoxy-11β-(2-dimethylaminoethanethio) prostaglandin of the E-type of Example 406 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11β-(2-dimethylaminoethanethio) and 9β-hydroxy-11β-(2-dimethylaminoethanethio) prostanoic analogs.

EXAMPLE 466

Treatment of the 11-deoxy-11α-(2-diethylaminoethanethio) prostaglandin of the E-type of Example 407 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(2-diethylaminoethanethio) and 9β-hydroxy-11α-(2-diethylaminoethanethio) prostanoic analogs.

EXAMPLE 467

Treatment of the 11-deoxy-11β-(2-diethylaminoethanethio) prostaglandin of the E-type of Example 407 with sodium borohydride by the procedure of Example 388 followed by silica-gel chromatography is productive of the corresponding 9α-hydroxy-11α-(2-diethylaminoethanethio) and 9β-hydroxy-11β-(2-diethylaminoethanethio) prostanoic analogs.

EXAMPLE 468 Preparation of 9-oxo-15α-hydroxy-16(R)methyl-5 cis, 10,13-trans-prostatrien-1-al

Treatment of 9-oxo-11α,15α-dihydroxy-16(R)methyl-5 cis, 13-trans-prostadien-1-al with mild acid by the procedure of Example 263 is productive of 9-oxo-15α-hydroxy-16(R)-methyl 5-cis, 10,13-trans-prostatrien-1-al.

EXAMPLE 469 Preparation of 9-oxo-15α-hydroxy-16-(S)-methyl-20-methoxy-5-cis, 10,13-trans-prostatrienoic acid.

Treatment of 9-oxo-11α,15α-dihydroxy 16(S)-methyl-20-methoxy-5-cis, 13-trans-prostadienoic acid [Arch. Int. Pharmacodyn. 226, 224-234(1977)] with mild acid by the procedure of Example 263 is productive of 9-oxo-15α-hydroxy-16(S)-methyl-20-methoxy-5-cis, 10,13-trans prostatrienoic acid.

EXAMPLE 470 This example illustrates the superior properties of an 11α-(2-hydroxyethylthio) compound of this invention compared to an 11α-(2-hydroxyethoxy) compound

The compounds dl-methyl ester of 11-deoxy-11α-(2-hydroxyethylthio)-15α-prostaglandin E₂ (hereinafter called Compound I) and dl-methyl ester of 11-deoxy-11α-(2-hydroxyethoxy)-15α-prostaglandin E₂ (hereinafter called Compound II) were submitted for testing in the modified Konzett procedure [J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995 (1968)].

The Modified Guinea Pig Konzett Assay measures the protective effects of experimental compounds against induced bronchospasms in guinea pigs.

Guinea pigs of either sex, weighing 300 to 500 g. are anesthetized by intraperitoneal injection of urethane at 1.5 g./kg. and curarized by intravenous injection of gallamine at 4 mg./kg. They are artificially ventilated through a tracheal cannula. Respiratory volume is adjusted according to the weight of the animal and the rate of the pump, in such a way as to obtain an insufflation pressure of 15-30 cm. of water.

The two jugular veins are catheterized, the first one being used for curarization and administration of the test compounds, the other one is used for the injection of the spasmogenic agent. Injections are made at selected speeds with a perfusion pump. The intratracheal pressure is measured with a transducer connected to the tracheal cannula and recorded on a polygraph.

Bronchial spasms are produced by intravenous injection of acetylcholine hydrochloride, histamine dihydrochloride or 5-hydroxy-tryptamine creatinine sulfate. The speed of injection of the spasmogenic solution and its concentration are chosen to give a dose (kept constant throughout the test) which is able to produce a consistant increase in the tracheal pressure. The injections are repeated every 5 minutes throughout the entire test by means of a program controlled automatic infusion syringe. When three successive control bronchoconstrictions of similar intensity are obtained, the animal is considered to be ready for the assay and receives the first dose of the test compound approximately two minutes later.

The compound being tested is suspended in 15% ethanol and injected through the jugular vein. The injection is repeated twice per animal at 15 minute intervals, so that three doses, in logarithmic progression, are assayed. Three spasms are recorded for each dose. The "bronchodilating" activity of each compound is assayed in at least four guinea pigs for each of the three spasmogenic substances. The amplitude of the three spasms (i.e. the difference between the maximum total tracheal pressure during the spasms and the normal insufflation pressure without spasm) following the administration of the drug are expressed in cm. of water.

When the average percent of variation (treated vs. control) of the first spasm following any dose of the compound reaches at least -50%, a regression line of the percent of variation versus the dose is computed in a semi-logarithmic system. The ED₅₀ (dose producing a -50% variation) is then calculated. The same determination is made for the second and third spasm following the administration of a dose of the test compound if at some dose the variation percent reaches -50%.

The results of this test on Compounds I and II appear in Table I below.

                  TABLE I                                                          ______________________________________                                                 ED.sub.50 (g./kg. × 10.sup.-6) vs.                                             Histamine            5-Hydroxytryp-                              Com-          Dihydro-   Acetylcholine                                                                            tamine Creat-                               pound Spasm   chloride   Hydrochloride                                                                            inine Sulfate                               ______________________________________                                         I     1       15.7       33.0      17.6                                              2       67.1       289       62.9                                              3       452                  153                                         II    1       152        506       119                                               2       707        3310      495                                               3       1460                 1280                                        ______________________________________                                    

A statistical analysis of the results indicates that Compound I is significantly more potent than Compound II as a bronchodilator.

While certain specific embodiments of the invention have been described with particularity, it should be recognized that modifications thereof will occur to those skilled in the art. Therefore, the scope of the invention is to be limited solely by the scope of the claims appended hereto. 

We claim:
 1. An optically active compound of the formula: ##STR39## where G is a moiety selected from the group consisting of: ##STR40## wherein Z is --(CH₂)₆ --; ##STR41## or ##STR42## R₁ is selected from the group consisting of hydroxy and C₁ -C₆ alkoxy; and R is a moiety selected from the group consisting of: ##STR43## wherein R₄ is selected from the group consisting of hydrogen and methyl and R₅ is selected from the group consisting of C₄ -C₇ alkyl and 2-cis(C₄ -C₆)alkenyl. The racemic mixture thereof; the mirror image therefore; and when R₁ is hydroxy, the pharmaceutically acceptable salts thereof.
 2. The compound according to claim 1, wherein Y is ##STR44##
 3. The compound according to claim 2, wherein R is: ##STR45##
 4. The compound according to claim 1, wherein Y is ##STR46##
 5. The compound according to claim 4 wherein R is ##STR47##
 6. The racemic compound and the nat. enantiomer thereof according to claim
 3. 7. The racemic compound and the nat. enantiomer thereof according to claim
 5. 8. A racemic compound according to claim 4, dl-9α,15α-DIHYDROXY-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID and the nat. enantiomer thereof.
 9. A racemic compound according to claim 4, dl-9α,15α-DIHYDROXY-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 10. A racemic compound according to claim 2, dl-9α,15α-DIHYDROXY-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 11. A racemic compound according to claim 2, dl-9α,15α-DIHYDROXY-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 12. A racemic compound according to claim 4, dl-9α,15α-DIHYDROXY-15-METHYL-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 13. A racemic compound according to claim 4, dl-9α,15α-DIHYDROXY-15-METHYL-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 14. A racemic compound according to claim 2, dl-9α,15α-DIHYDROXY-15-METHYL-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 15. A racemic compound according to claim 2, dl-9α,15α-DIHYDROXY-15-METHYL-11α(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 16. A racemic compound according to claim 4 dl-9β,15α-DIHYDROXY-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 17. A racemic compound according to claim 4, dl-9β,15 α-DIHYDROXY-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 18. A racemic compound according to claim 20, dl-9β,15α-DIHYDROXY-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 19. A racemic compound according to claim 20, dl-9β,15α-DIHYDROXY-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 20. A racemic compound according to claim 4, dl-9β,15α-DIHYDROXY-15-METHYL-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 21. A racemic compound according to claim 4, dl-9β,15α-DIHYDROXY-15-METHYL-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 22. A racemic compound according to claim 20, dl-9β,15α-DIHYDROXY-15-METHYL-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 23. A racemic compound according to claim 20, dl-9β,15α-DIHYDROXY-15-METHYL-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 24. A racemic compound according to claim 4, dl-9α,15α-DIHYDROXY-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 25. A racemic compound according to claim 4 dl-9α,15α-DIHYDROXY-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 26. A racemic compound according to claim 20, dl-9α,15α-DIHYDROXY-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 27. A racemic compound according to claim 20, dl-9α,15α-DIHYDROXY-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 28. A racemic compound according to claim 4, dl-9α,15α-DIHYDROXY-15-METHYL-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 29. A racemic compound according to claim 4, dl-9α,15α-DIHYDROXY-15-METHYL-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 30. A racemic compound according to claim 20, dl-9α,15α-DIHYDROXY-15-METHYL-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 31. A racemic compound according to claim 20, dl-9α,15α-DIHYDROXY-15-METHYL-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 32. A racemic compound according to claim 4, dl-9β,15α-DIHYDROXY-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 33. A racemic compound according to claim 4, dl-9β,15α-DIHYDROXY-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 34. A racemic compound according to claim 20, dl-9β,15α-DIHYDROXY-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 35. A racemic compound according to claim 20, dl-9β,15α-DIHYDROXY-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 36. A racemic compound according to claim 22, dl-9β,15α-DIHYDROXY-15-METHYL-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 37. A racemic compound according to claim 22, dl-9β,15α-DIHYDROXY-15-METHYL-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 38. A racemic compound according to claim 20, dl-9β,15α-DIHYDROXY-15-METHYL-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 39. A racemic compound according to claim 20, dl-9β,15α-DIHYDROXY-15-METHYL-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 40. A racemic compound according to claim 22, dl-15α-HYDROXY-9-OXO-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 41. A racemic compound according to claim 22, dl-15α-HYDROXY-9-OXO-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 42. A racemic compound according to claim 20, dl-15α-HYDROXY-9-OXO-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 43. A racemic compound according to claim 20, dl-15α-HYDROXY-9-OXO-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 44. A racemic compound according to claim 4, dl-15α-HYDROXY-9-OXO-15-METHYL-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 45. A racemic compound according to claim 4, dl-15α-HYDROXY-9-OXO-15-METHYL-11α-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 46. A racemic compound according to claim 20, dl-15α-HYDROXY-9-OXO-15-METHYL-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 47. A racemic compound according to claim 20, dl-15α-HYDROXY-9-OXO-15-METHYL-11α-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 48. A racemic compound according to claim 4, dl-15α-HYDROXY-9-OXO-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 49. A racemic compound according to claim 4, dl-15α-HYDROXY-9-OXO-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 50. A racemic compound according to claim 20, dl-15α-HYDROXY-9-OXO-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 51. A racemic compound according to claim 20, dl-15α-HYDROXY-9-OXO-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof.
 52. A racemic compound according to claim 4, dl-15α-HYDROXY-9-OXO-15-METHYL-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID.
 53. A racemic compound according to claim 4, dl-15α-HYDROXY-9-OXO-15-METHYL-11β-(2-HYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER.
 54. A racemic compound according to claim 20, dl-15α-HYDROXY-9-OXO-15-METHYL-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID, and the nat. enantiomer thereof.
 55. A racemic compound according to claim 20, dl-15α-HYDROXY-9-OXO-15-METHYL-11β-(2,3-DIHYDROXYPROPYLTHIO)-13-trans PROSTENOIC ACID METHYL ESTER, and the nat. enantiomer thereof. 